European Heart Journal (2018) 00,1–69 ESC GUIDELINES doi:10.1093/eurheartj/ehy037
2018 ESC Guidelines for the diagnosis and management of syncope The Task Force for the diagnosis and management of syncope of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) Endorsed by: European Academy of Neurology (EAN), European Federation of Autonomic Societies (EFAS), European Federation of Internal Medicine (EFIM), European Union Geriatric Medicine Society (EUGMS), European Society of Emergency Medicine (EuSEM)
Authors/Task Force Members: Michele Brignole* (Chairperson) (Italy), Angel Moya* (Co-chairperson) (Spain), Frederik J. de Lange (The Netherlands), Jean-Claude Deharo (France), Perry M. Elliott (UK), Alessandra Fanciulli (Austria), Artur Fedorowski (Sweden), Raffaello Furlan (Italy), Rose Anne Kenny (Ireland), Alfonso Mart ın (Spain), Vincent Probst (France), Matthew J. Reed (UK), Ciara P.Rice (Ireland), Richard Sutton (Monaco), Andrea Ungar (Italy), and J. Gert van Dijk (The Netherlands)
* Corresponding authors: Michele Brignole, Department of Cardiology, Ospedali Del Tigullio, Via Don Bobbio 25, IT-16033 Lavagna, (GE) Italy. Tel: þ39 0185 329 567, Fax: þ39 0185 306 506, Email: [email protected]; Angel Moya, Arrhythmia Unit, Hospital Vall d’Hebron, P Vall d’Hebron 119-129, ES-08035 Barcelona, Spain. Tel: þ34 93 2746166, Fax: þ34 93 2746002, Email: [email protected]. ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix. 1 Representing the European Academy of Neurology (EAN) 2 Representing the European Federation of Internal Medicine (EFIM) 3 Representing the European Society of Emergency Medicine (EuSEM) ESC entities having participated in the development of this document: Associations: European Heart Rhythm Association (EHRA) Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care Working Groups: Myocardial and Pericardial Diseases The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]). Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidenceavailable at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom- mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour- aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
VC The European Society of Cardiology 2018. All rights reserved. For permissions please email: [email protected]
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 2 ESC Guidelines
Document Reviewers: Adam Torbicki (CPG Review Coordinator) (Poland), Javier Moreno (CPG Review Coordinator) (Spain), Victor Aboyans (France), Stefan Agewall (Norway), Riccardo Asteggiano (Italy), Jean-Jacques Blanc (France), Natan Bornstein1 (Israel), Serge Boveda (France), He´ ctor Bueno (Spain), Haran Burri (Switzerland), Antonio Coca (Spain), Jean-Philippe Collet (France), Giorgio Costantino2 (Italy), Ernesto D ıaz-Infante (Spain), Victoria Delgado (The Netherlands), Faas Dolmans (The Netherlands), Oliver Gaemperli (Switzerland), Jacek Gajek (Poland), Gerhard Hindricks (Germany), Josef Kautzner (Czech Replublic), Juhani Knuuti (Finland), Piotr Kulakowski (Poland), Ekaterini Lambrinou (Cyprus), Christophe Leclercq (France), Philippe Mabo (France), Carlos A. Morillo (Canada), Massimo Francesco Piepoli (Italy), Marco Roffi (Switzerland), Win K. Shen (USA), Iain A. Simpson (UK), Martin Stockburger (Germany), Peter Vanbrabant3 (Belgium), Stephan Windecker (Switzerland), and Jose Luis Zamorano (Spain)
The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website http://www.escardio.org/guidelines.
...... Keywords Guidelines • Syncope • Transient loss of consciousness • Vasovagal syncope • Reflex syncope • Orthostatic hypotension • Cardiac syncope • Sudden cardiac death • Electrophysiological study • Prolonged ECG monitoring • Tilt testing • Carotid sinus massage • Cardiac pacing • Implantable cardioverter defibrillator • Syncope unit • Emergency department
. . 4.2.4.1In-hospitalmonitoring...... 23 Table of Contents . . 4.2.4.2Holtermonitoring...... 23 1.Preamble...... 4 . 4.2.4.3 Prospective external event recorders...... 23 . 2.Introduction...... 5 . 4.2.4.4Smartphoneapplications...... 23 2.1Whatisnewinthe2018version?...... 6 . 4.2.4.5Externallooprecorders...... 23 . 3. Definitions, classification, and pathophysiology ...... 7 . 4.2.4.6Remote(athome)telemetry...... 23 3.1Definitions...... 7 . 4.2.4.7Implantablelooprecorders...... 23 . 3.2 Classification and pathophysiology of syncope and transient . 4.2.4.8Diagnosticcriteria...... 23 lossofconsciousness...... 8 . 4.2.5Videorecordinginsuspectedsyncope...... 25 . 3.2.1Syncope...... 8 . 4.2.5.1In-hospitalvideorecording...... 25 3.2.2 Non-syncopal forms of (real or apparent) transient . 4.2.5.2Homevideorecording...... 25 . lossofconsciousness...... 8 . 4.2.6Electrophysiologicalstudy...... 25 4. Diagnostic evaluation and management according to . 4.2.6.1 Asymptomatic sinus bradycardia – suspected . riskstratification...... 10 . sinusarrestcausingsyncope...... 25 . 4.1Initialevaluation...... 10 . 4.2.6.2 Syncope in bifascicular bundle branch block 4.1.1Diagnosisofsyncope...... 11 . (impending high-degree atrioventricular block) ...... 25 . 4.1.2 Management of syncope in the emergency department . 4.2.6.3Suspectedtachycardia...... 25 basedonriskstratification...... 13 . 4.2.7 Endogenous adenosine and other biomarkers...... 27 . 4.2Diagnostictests...... 17 . 4.2.7.1 Adenosine (triphosphate) test and plasma 4.2.1Carotidsinusmassage...... 17 . concentration...... 27 . 4.2.2Orthostaticchallenge...... 18 . 4.2.7.2Cardiovascularbiomarkers...... 27 4.2.2.1Activestanding...... 18 . 4.2.7.3Immunologicalbiomarkers...... 27 . 4.2.2.2Tilttesting...... 20 . 4.2.8Echocardiography...... 27 4.2.3Basicautonomicfunctiontests...... 21 . 4.2.8.1Exercisestressechocardiography...... 27 . 4.2.3.1Valsalvamanoeuvre...... 21 . 4.2.9Exercisestresstesting...... 28 4.2.3.2Deepbreathing...... 21 . 4.2.10Coronaryangiography...... 28 . 4.2.3.3Otherautonomicfunctiontests...... 21 . 5.Treatment...... 28 4.2.3.4 Twenty-four-hour ambulatory and home . 5.1 General principles of treatment of syncope...... 28 . bloodpressuremonitoring...... 21 . 5.2Treatmentofreflexsyncope...... 29 4.2.4 Electrocardiographic monitoring (non-invasive . 5.2.1Educationandlifestylemodifications...... 29 . andinvasive) ...... 23 . 5.2.2 Discontinuation/reduction of hypotensive therapy ...... 31
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 3
. 5.2.3Physicalcounter-pressuremanoeuvres...... 31 . 6.1.1Comorbidityandpolypharmacy...... 44 . 5.2.4Tilttraining...... 31 . 6.1.2Falls...... 45 5.2.5Pharmacologicaltherapy...... 31 . 6.1.3 Cognitive assessment and physical performance tests...... 45 . 5.2.5.1Fludrocortisone...... 31 . 6.2Syncopeinpaediatricpatients...... 46 5.2.5.2Alpha-agonists...... 32 . 6.2.1Diagnosticevaluation...... 46 . 5.2.5.3Beta-blockers...... 32 . 6.2.2Therapy...... 46 5.2.5.4Otherdrugs...... 32 . 7. Psychogenic transient loss of consciousness and its evaluation...... 46 . 5.2.5.5 Emerging new therapies in specific subgroups ...... 32 . 7.1Diagnosis...... 46 5.2.6Cardiacpacing...... 32 . 7.1.1Historicalcriteriaforattacks...... 46 . 5.2.6.1 Evidence from trials in suspected or . 7.1.2 Documentation of key features during an attack...... 46 certain reflex syncope and electrocardiogram- . 7.1.2.1 Management of psychogenic pseudosyncope ...... 47 . documentedasystole...... 32 . 8.Neurologicalcausesandmimicsofsyncope...... 47 5.2.6.2 Evidence from trials in patients with carotid . 8.1Clinicalconditions...... 47 . sinussyndrome...... 33 . 8.1.1Autonomicfailure...... 47 5.2.6.3 Evidence from trials in patients with tilt-induced . 8.1.2Epilepsyandictalasystole...... 47 . vasovagalsyncope...... 33 . 8.1.3Cerebrovasculardisorders...... 48 5.2.6.4 Evidence from trials in patients with . 8.1.4Migraine...... 49 . adenosine-sensitivesyncope...... 34 . 8.1.5Cataplexy...... 49 5.2.6.5Choiceofpacingmode...... 34 . 8.1.6Dropattacks...... 49 . 5.2.6.6 Selection of patients for pacing and . 8.2Neurologicaltests...... 49 proposedalgorithm...... 34 . 8.2.1Electroencephalography...... 50 . 5.3 Treatment of orthostatic hypotension and orthostatic intolerance . 8.2.2 Brain computed tomography and magnetic syndromes...... 37 . resonanceimaging...... 50 . 5.3.1Educationandlifestylemeasures...... 37 . 8.2.3Neurovascularstudies...... 50 . 5.3.2Adequatehydrationandsaltintake...... 37 . 8.2.4Bloodtests...... 50 5.3.3 Discontinuation/reduction of vasoactive drugs ...... 37 . 9.Organizationalaspects...... 50 . 5.3.4Counter-pressuremanoeuvres...... 37 . 9.1 Syncope (transient loss of consciousness) management unit . . . . . 50 5.3.5 Abdominal binders and/or support stockings...... 37 . 9.1.1Definitionofasyncopeunit...... 50 . 5.3.6Head-uptiltsleeping...... 37 . 9.1.2Definitionofsyncopespecialist...... 50 5.3.7Midodrine...... 37 . 9.1.3Goalofasyncopeunit...... 50 . 5.3.8Fludrocortisone...... 37 . 9.1.4Modelofasyncopeunit...... 52 5.3.9Additionaltherapies...... 38 . 9.1.5Accessandreferralstoasyncopeunit...... 52 . 5.3.10 Emerging new pharmacological therapy in specific . 9.1.6Outcomesandqualityindicators...... 52 subgroups...... 38 . 9.2 The clinical nurse specialist in the syncope unit...... 52 . 5.4Cardiacarrhythmiasastheprimarycause...... 38 . 9.2.1Definition...... 52 5.4.1 Syncope due to intrinsic sinoatrial or atrioventricular . 9.2.2 Role and skills of the clinical nurse specialist ...... 53 . conductionsystemdisease...... 38 . 10.Keymessages...... 54 5.4.1.1Sinusnodedisease...... 38 . 11.Gapsinevidenceandareasforfutureresearch...... 54 . 5.4.1.2 Atrioventricular conduction system disease...... 39 . 12. ‘What to do’ and ‘what not to do’ messages from the 5.4.1.3 Bundle branch block and unexplained syncope...... 39 . Guidelines...... 56 . 5.4.2 Syncope due to intrinsic cardiac tachyarrhythmias ...... 40 . 13. Supplementary Data and Web Practical Instructions...... 58 5.4.2.1 Paroxysmal supraventricular tachycardia...... 41 . 14.Appendix...... 58 . 5.4.2.2 Paroxysmal ventricular tachycardia ...... 41 . 15.References...... 59 5.5 Treatment of syncope secondary to structural cardiac, . . cardiopulmonary, and great vessel disease ...... 42 . . 5.6 Treatment of unexplained syncope in patients at high risk of . Abbreviations and acronyms suddencardiacdeath...... 42 . . 5.6.1Definition...... 42 . ABPM Ambulatory blood pressure monitoring 5.6.2Leftventricularsystolicdysfunction...... 42 . AF Atrial fibrillation . 5.6.3Hypertrophiccardiomyopathy...... 43 . ARVC Arrhythmogenic right ventricular cardiomyopathy 5.6.4 Arrhythmogenic right ventricular cardiomyopathy...... 43 . ATP Adenosine triphosphate . 5.6.5 Patients with inheritable arrhythmogenic disorders ...... 43 . AV Atrioventricular 5.6.5.1LongQTsyndrome...... 43 . AVID Antiarrhythmics versus Implantable . 5.6.5.2Brugadasyndrome...... 44 . Defibrillators trial 5.6.5.3Otherforms...... 44 . BBB Bundle branch block . 6.Specialissues...... 44 . BNP B-type natriuretic peptide 6.1 Syncope in patients with comorbidity and frailty ...... 44 . BP Blood pressure
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 4 ESC Guidelines
. b.p.m. Beats per minute . 1. Preamble . CI Confidence interval . CI-CSS Cardioinhibitory carotid sinus syndrome . Guidelines summarize and evaluate available evidence with the aim of . assisting health professionals in selecting the best management strat- CPG Committee for Practice Guidelines . CRT-D Cardiac resynchronization therapy defibrillator . egies for an individual patient with a given condition. Guidelines and . their recommendations should facilitate decision making of health CSM Carotid sinus massage . CSS Carotid sinus syndrome . professionals in their daily practice. However, the final decisions con- . DCM Dilated cardiomyopathy . cerning an individual patient must be made by the responsible health . professional(s) in consultation with the patient and caregiver as DDD-PM Dual chamber pacemaker . ECG Electrocardiogram/electrocardiographic . appropriate. . A great number of guidelines have been issued in recent years by ED Emergency department . EEG Electroencephalogram . the European Society of Cardiology (ESC), as well as by other soci- . eties and organisations. Because of the impact on clinical practice, EFAS European Federation of Autonomic Societies . EFIM European Federation of Internal Medicine . quality criteria for the development of guidelines have been estab- . lished in order to make all decisions transparent to the user. The rec- EHRA European Heart Rhythm Association . ENS European Neurological Society . ommendations for formulating and issuing ESC Guidelines can be . found on the ESC website (http://www.escardio.org/Guidelines-&- EPS Electrophysiological study . ESC European Society of Cardiology . Education/Clinical-Practice-Guidelines/Guidelines-development/Writ . ing-ESC-Guidelines). ESC Guidelines represent the official position of EUGMS European Union Geriatric Medicine Society . EuSEM European Society of Emergency Medicine . the ESC on a given topic and are regularly updated. . Members of this Task Force were selected by the ESC, including HBPM Home blood pressure monitoring . HCM Hypertrophic cardiomyopathy . representation from its relevant ESC sub-specialty groups, in order . to represent professionals involved with the medical care of patients HR Heart rate . ICD Implantable cardioverter defibrillator . with this pathology. Selected experts in the field undertook a com- . prehensive review of the published evidence for management of a ILR Implantable loop recorder . ISSUE International Study on Syncope of . given condition according to ESC Committee for Practice Guidelines . (CPG) policy. A critical evaluation of diagnostic and therapeutic pro- Unknown Etiology . L-DOPA L-3,4-dihydroxyphenylalanine . cedures was performed, including assessment of the risk–benefit . LOC Loss of consciousness . ratio. The level of evidence and the strength of the recommendation . of particular management options were weighed and graded accord- LQTS Long QT syndrome . LVEF Left ventricular ejection fraction . ing to predefined scales, as outlined in Tables 1 and 2. . The experts of the writing and reviewing panels provided declar- MRI Magnetic resonance imaging . NYHA New York Heart Association . ation of interest forms for all relationships that might be perceived as . real or potential sources of conflicts of interest. These forms were OH Orthostatic hypotension . PC-Trial Physical Counterpressure Manoeuvres Trial . compiled into one file and can be found on the ESC website (http:// . www.escardio.org/guidelines). Any changes in declarations of interest PCM Physical counter-pressure manoeuvres . PNES Psychogenic non-epileptic seizures . that arise during the writing period were notified to the ESC and . updated. The Task Force received its entire financial support from POST Prevention of Syncope Trial . POTS Postural orthostatic tachycardia syndrome . the ESC without any involvement from the healthcare industry. . The ESC CPG supervises and coordinates the preparation of new PPS Psychogenic pseudosyncope . RCT Randomized controlled trial . Guidelines. The Committee is also responsible for the endorsement . process of these Guidelines. The ESC Guidelines undergo extensive SCD Sudden cardiac death . SNRT Sinus node recovery time . review by the CPG and external experts. After appropriate revisions . the Guidelines are approved by all the experts involved in the Task SU Syncope unit . SUP Syncope Unit Project . Force. The finalized document is approved by the CPG for publica- . tion in the European Heart Journal. The Guidelines were developed SVT Supraventricular tachycardia . TIA Transient ischaemic attack . after careful consideration of the scientific and medical knowledge . and the evidence available at the time of their dating. t.i.d. Ter in die (three times daily) . TLOC Transient loss of consciousness . The task of developing ESC Guidelines also includes the creation of . educational tools and implementation programmes for the recommen- TNG Trinitroglycerin . VA Ventricular arrhythmia . dations including condensed pocket guideline versions, summary slides, . VF Ventricular fibrillation . booklets with essential messages, summary cards for non-specialists . and an electronic version for digital applications (smartphones, etc.). VT Ventricular tachycardia . VVS Vasovagal syncope . These versions are abridged and thus, if needed, one should always . refer to the full-text version, which is freely available via the ESC
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 5
Table 1 Classes of recommendations
Table 2 Levels of evidence
. websiteandhostedontheEHJwebsite.TheNationalSocietiesofthe . is also the health professional’s responsibility to verify the rules and ESC are encouraged to endorse, translate and implement all ESC . regulations applicable to drugs and devices at the time of prescription. . Guidelines. Implementation programmes are needed because it has . . been shown that the outcome of disease may be favourably influenced . by the thorough application of clinical recommendations. . . 2. Introduction Surveys and registries are needed to verify that real-life daily prac- . tice is in keeping with what is recommended in the guidelines, thus . The first ESC Guidelines for the management of syncope were pub- . completing the loop between clinical research, writing of guidelines, . lished in 2001, with subsequent versions in 2004 and 2009. In March disseminating them and implementing them into clinical practice. . 2015, the ESC CPG considered that there were enough new data to . Health professionals are encouraged to take the ESC Guidelines fully . justify the production of new Guidelines. into account when exercising their clinical judgment, as well as in the . The most important aspect characterizing this document is the . determination and the implementation of preventive, diagnostic, or . composition of the Task Force, which is truly multidisciplinary. therapeutic medical strategies. However, the ESC Guidelines do not . Cardiologists form a minority of the panel; experts in emergency . override in any way whatsoever the individual responsibility of health . medicine, internal medicine and physiology, neurology and auto- professionals to make appropriate and accurate decisions in consider- . nomic diseases, geriatric medicine, and nursing cover all aspects of . ation of each patient’s health condition and in consultation with that pa- . management of the various forms of syncope and transient loss of tient or the patient’s caregiver where appropriate and/or necessary. It . consciousness (TLOC).
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 6 ESC Guidelines
. Compared with the previous versions of these Guidelines, the . The document aims to be patient-orientated and focused on ther- 2018 document contains Supplementary Data as an integral part. . apy, and to reduce the risk of recurrence and the life-threatening . While the print text mainly aims to give formal evidence-based rec- . consequences of syncope recurrence. For this purpose, even in the ommendations according to the standardized rules of the ESC, this . absence of strong evidence from trials, we give as much advice as . new web-only feature allows expansion of the content to practical . possible on the most appropriate therapy based on the practical ex- issues, and aims to fill the gap between the best available scientific evi- . pertise of the members of the Task Force (‘Our patients seek solutions, . dence and the need for dissemination of these concepts into clinical . not only explanations’). When possible, we provide therapeutic and practice (‘We have the knowledge, we need to teach it’). Thanks to the . decision-making algorithms. . Supplementary Data further explanation on specific points is given, . Finally, we recognize that one major challenge in syncope manage- . and thanks to the Web Practical Instructions advice is given on how . ment is the reduction of inappropriate admissions and inappropriate to evaluate patients with loss of consciousness (LOC), and how to . use of tests while maintaining the safety of the patient. We give strong . perform and interpret tests properly; whenever possible, we provide . focus to pathways and organizational issues (‘We have the knowledge; tracings, videos, flow charts, and checklists. . we need to apply it’). In particular, we propose a care pathway for the .
Figure 1 What is new in the 2018 syncope Guidelines? AA = antiarrhythmic; AF = atrial fibrillation; ARVC = arrhythmogenic right ventricular car- diomyopathy; CSM = carotid sinus massage; ECG = electrocardiogram; ED = emergency department; LVEF = left ventricular ejection fraction; EPS = electrophysiological study; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; OH = orthostatic hypotension; PCM = physical counter-pressure manoeuvres; POTS = postural orthostatic tachycardia syndrome; PPS = psycho- genic pseudosyncope; SNRT = sinus node recovery time; SU = syncope unit; SVT = supraventricular tachycardia; VT = ventricular tachycardia.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 7
Central illustration New/revised concepts in the management of syncope. ECG = electrocardiogram; ED = emergency department; ICD = implantable cardioverter defibrillator; SCD = sudden cardiac death.
. management of patients with TLOC from their arrival in the emer- . TLOC is defined as a state of real or apparent LOC with loss of . • gency department (ED), and give practical instructions on how to set . awareness, characterized by amnesia for the period of uncon- . sciousness, abnormal motor control, loss of responsiveness, and up outpatient syncope clinics (syncope units) aimed at reducing hos- . pitalization, under- and misdiagnoses, and costs. . a short duration. . . The two main groups of TLOC are ‘TLOC due to head trauma’ . 2.1 What is new in the 2018 version? . and ‘non-traumatic TLOC’ (Figure 2). Traumatic TLOC will not be The changes in recommendations made in the 2018 version com- . considered further in this document, so TLOC will be used to mean . pared with the 2009 version, the new recommendations, and the . non-traumatic TLOC. most important new/revised concepts are summarized in Figure 1. . The clinical features characterizing TLOC are usually derived from his- . . tory taking from patients and eyewitnesses. Specific characteristics that . aid diagnosis are outlined in section 3 of the Web Practical Instructions. . 3. Definitions, classification, and . TLOC groups are defined using pathophysiology: the qualifying cri- . terion for syncope is cerebral hypoperfusion; for epileptic seizures, it . pathophysiology . is abnormal excessive brain activity; and for psychogenic TLOC it is . the psychological process of conversion. The syncope definition rests 3.1 Definitions . . on pathophysiology because no set of clinical features encompasses • Syncope is defined as TLOC due to cerebral hypoperfusion, char- . all forms of syncope while also excluding all epileptic seizures and acterized by a rapid onset, short duration, and spontaneous com- . . psychogenic TLOC events. plete recovery. . . • The adjective presyncope is used to indicate symptoms and signs Syncope shares many clinical features with other disorders; it . . that occur before unconsciousness in syncope. Note that the therefore presents in many differential diagnoses. This group of dis- . noun presyncope is often used to describe a state that resembles orders is labelled TLOC. . the prodrome of syncope, but which is not followed by LOC.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 8 ESC Guidelines
Generalized: Psychogenic - Tonic pseudosyncope (PPS) - Clonic Psychogenic non-epileptic - Tonic-clonic seizures (PNES) - Atonic
Figure 2 Syncope in the context of transient loss of consciousness. Non-traumatic transient loss of consciousness is classified into one of four groupings: syncope, epileptic seizures, psychogenic transient loss of consciousness, and a miscellaneous group of rare causes. This order represents their rate of occurrence. Combinations occur; e.g. non-traumatic transient loss of consciousness causes can cause falls with concussion, in which case transient loss of consciousness is both traumatic and non-traumatic. TIA = transient ischaemic attack; TLOC = transient loss of consciousness.
. A variety of terms are used that generally do not match the definitions . ‘vasodepressive type’ of reflex syncope, seen in the outer ring in in this document closely enough to be used as synonyms of the defined . Figure 3. The second is a functional impairment, and the third a struc- . terms. For example, a ‘faint’ approximately conforms to syncope but . tural impairment of the autonomic nervous system, with drug- emphasizes vasovagal syncope (VVS) over other forms. A glossary of un- . induced, primary, and secondary autonomic failure in the outer ring. . certaintermsisshowninsection1oftheWeb Practical Instructions. . In autonomic failure, there is insufficient sympathetic vasoconstriction . in response to the upright position. 3.2 Classification and pathophysiology of . . There are four primary causes of low cardiac output. The first is syncope and transient loss of . a reflex bradycardia, known as cardioinhibitory reflex syncope. . consciousness . The second concerns cardiovascular causes: arrhythmia, struc- 3.2.1 Syncope . tural disease including pulmonary embolism, and pulmonary . Table 3 provides a classification of the principal causes of syncope, . hypertension. The third is inadequate venous return due to vol- emphasizing groups of disorders with common pathophysiology, . ume depletion or venous pooling. Finally, chronotropic and ino- . presentation, and risk. Clinical features, epidemiology, prognosis, im- . tropic incompetence through autonomic failure may impair . cardiac output. pact on quality of life, and economic issues are shown in section 2 of . the Web Practical Instructions. . Note that these primary mechanisms may interact in different . ways: firstly, venous pooling and inadequate venous return is also a The pathophysiological classification centres on a fall in systemic . blood pressure (BP) with a decrease in global cerebral blood flow as . factor that can trigger an inappropriate reflex in orthostatic reflex . syncope; secondly, a low total peripheral resistance may cause ven- the defining characteristic of syncope. Figure 3 shows low BP and glo- . bal cerebral hypoperfusion as the central final common pathway of . ous pooling of blood below the diaphragm, in turn decreasing venous . syncope. A sudden cessation of cerebral blood flow for as short as . return and consequently cardiac output. 6–8 s can cause complete LOC. A systolic BP of 50–60 mmHg at . The three main groups of syncope, i.e. reflex, cardiovascular, and . heart level, i.e. 30–45 mmHg at brain level in the upright position, will . secondary to orthostatic hypertension (OH), are shown outside the cause LOC.8,9 . rings in Figure 3. Both reflex syncope and OH span the two main . Systemic BP is the product of cardiac output and total peripheral . pathophysiological mechanisms. resistance; a fall in either can cause syncope. However, in syncope, . . both mechanisms often act together to a varying degree. . 3.2.2 Non-syncopal forms of (real or apparent) transient There are three primary causes of a low total peripheral resist- . loss of consciousness . ance. The first is decreased reflex activity causing vasodilatation . Only those forms of epilepsy in which normal motor control is lost, through withdrawal of sympathetic vasoconstriction: this is the . so patients may fall, are included in Figure 2. These are tonic, clonic,
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 9
Table 3 Classification of syncope
Reflex (neurally mediated) syncope
Vasovagal: - orthostatic VVS: standing, less common sitting - emotional: fear, pain (somatic or visceral), instrumentation, blood phobia Situational: - micturition - gastrointestinal stimulation (swallow, defaecation) - cough, sneeze - post-exercise - others (e.g. laughing, brass instrument playing) Carotid sinus syndrome Non-classical forms (without prodromes and/or without apparent triggers and/or atypical presentation)
Syncope due to OH
Note that hypotension may be exacerbated by venous pooling during exercise (exercise-induced), after meals (postprandial hypotension), and after prolonged bed rest (deconditioning). Drug-induced OH (most common cause of OH): - e.g. vasodilators, diuretics, phenothiazine, antidepressants Volume depletion: - haemorrhage, diarrhoea, vomiting, etc. Primary autonomic failure (neurogenic OH): - pure autonomic failure, multiple system atrophy, Parkinson’s disease, dementia with Lewy bodies Secondary autonomic failure (neurogenic OH): - diabetes, amyloidosis, spinal cord injuries, auto-immune autonomic neuropathy, paraneoplastic autonomic neuropathy, kidney failure
Cardiac syncope
Arrhythmia as primary cause: Bradycardia: - sinus node dysfunction (including bradycardia/tachycardia syndrome) - atrioventricular conduction system disease Tachycardia: - supraventricular - ventricular Structural cardiac: aortic stenosis, acute myocardial infarction/ischaemia, hypertrophic cardiomyopathy, cardiac masses (atrial myxoma, tumours, etc.), pericardial disease/tamponade, congenital anomalies of coronary arteries, prosthetic valve dysfunction Cardiopulmonary and great vessels: pulmonary embolus, acute aortic dissection, pulmonary hypertension
Remarks
• All forms of syncope, but mostly reflex syncope and OH, are more likely to occur or are more severe when various factors are present: medica- tion causing low BP (due to vasodilatation or hypovolaemia), alcohol use, volume depletion (haemorrhage, low fluid intake, diarrhoea, vomiting), pulmonary diseases causing reduction in brain oxygen supply, environmental factors (thermal stress). • There are two main pathophysiological mechanisms in reflex syncope. “Vasodepression” refers to conditions in which insufficient sympathetic vasoconstriction results in hypotension.1,2 “Cardioinhibition” is used when bradycardia or asystole predominates, reflecting a shift towards para- sympathetic predominance. The haemodynamic pattern, i.e. cardioinhibitory, vasodepressive, or both, is independent of the trigger evoking reflex syncope. For example, micturition syncope and orthostatic VVS may equally well present as cardioinhibitory or as vasodepressor syncope • The non-classical form of reflex syncope involves a heterogeneous group of patients. The term is used to describe reflex syncope that occurs with uncertain or apparently absent triggers and/or atypical presentation. The diagnosis of reflex syncope is probable when other causes of syn- cope are excluded (absence of structural heart disease) and/or symptoms are reproduced in the tilt test.3 At present, this group also contains syncope associated with low adenosine plasma levels4,5 • The cardiovascular causes of orthostatic intolerance include classical OH, initial OH, delayed OH, POTS, and VVS, which in this context can be called orthostatic VVS.6,7 Syndromes of orthostatic intolerance that may cause syncope are presented in Web Practical Instruction section 2.
BP = blood pressure; OH = orthostatic hypotension; POTS = postural orthostatic tachycardia syndrome; VVS = vasovagal syncope.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 10 ESC Guidelines
Table 4 Conditions that may be incorrectly diagnosed as syncope
Condition Characteristic features that distin- guish from syncope
Generalized seizures See section 8, Table 10.
Complex partial seiz- No falls, yet unresponsive and later ures, absence epilepsy amnesia
PPS or Duration of apparent LOC “pseudocoma” lasting many minutes to hours; high frequency, up to several times a day
Falls without TLOC No unresponsiveness or amnesia
Cataplexy Falls with flaccid paralysis and non- responsive, yet no later amnesia
Intracerebral or sub- Consciousness may be progressively arachnoid reduced rather than immediately haemorrhage lost. Accompanying severe head- Figure 3 Pathophysiological basis of the classification of syncope. ache, other neurological signs ANS = autonomic nervous system; auton. = autonomic; BP = blood pressure; OH = orthostatic hypotension; periph. = Vertebrobasilar TIA Always focal neurological signs and peripheral; resist. = resistance. symptoms, usually without LOC; if consciousness is lost this usually lasts longer than in TLOC. tonic-clonic, and atonic generalized seizures, and can be classified as Carotid TIA Consciousness is for all practical primary or secondary. The forms of epilepsy in which people remain purposes not lost in carotid TIAs, actively upright, i.e. sitting or standing (e.g. complex partial seizures but there are pronounced focal or absence epilepsy) are not regarded as TLOC, but sometimes they neurological signs and symptoms are incorrectly diagnosed as syncope. Psychogenic TLOC consists of two forms: one resembles epileptic Subclavian steal Associated with focal neurological seizures (psychogenic non-epileptic seizures [PNES]) and one, with- syndrome signs out gross movements, resembles syncope (psychogenic pseudosyn- Metabolic disorders Duration much longer than in cope [PPS]). including hypogly- TLOC; consciousness may be im- The rare causes of TLOC only seldomly cause confusion with the caemia, hypoxia, paired instead of lost main TLOC forms, probably because in most cases they differ hyperventilation with enough clinically to be clearly not syncope. Both vertebrobasilar tran- hypocapnia sient ischaemic attacks (TIAs) and subclavian steal syndrome are associated with focal neurological signs. A subarachnoid haemor- Intoxication Duration much longer than in rhage may present with a short LOC, but the associated abrupt ex- TLOC; consciousness may be im- treme headache suggests the cause. In cyanotic breath-holding spells, paired instead of lost expiratory apnoea with hypoxia is the primary mechanism.10 So- Cardiac arrest LOC yet no spontaneous recovery called ‘pallid breath-holding spells’ in children do not constitute a pri- 11 mary respiratory problem, but are cardioinhibitory reflex syncope. Coma Duration much longer than TLOC Table 4 lists the main features that distinguish syncope from dis- orders that may be mistaken for syncope. LOC = loss of consciousness; PPS = psychogenic pseudosyncope; TIA = transient ischaemic attack; TLOC = transient loss of consciousness. 4. Diagnostic evaluation and management according to risk . . with possible TLOC, history taking should first establish whether there stratification . . was indeed a TLOC. Often, this allows a distinction between the major . TLOC groups. The flow diagram for the evaluation of TLOC is shown in 4.1 Initial evaluation . . Figure 4. The initial evaluation should answer key questions: The clinical features characterizing TLOC are usually derived from his- . tory taking from patients and eyewitnesses. When a patient first presents . (1) Was the event TLOC?
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 11
Figure 4 Flow diagram for the initial evaluation and risk stratification of patients with syncope. BP = blood pressure; ECG = electrocardiogram; H&P exam = history and physical examination; TLOC = transient loss of consciousness.
. 12 (2) In case of TLOC, is it of syncopal or non-syncopal origin? . approximately 60% of cases. For non-syncopal TLOC, refer to sec- (3) In case of suspected syncope, is there a clear aetiological diagnosis . tions 7 and 8. . (see section 4.1.1)? . . 4.1.1 Diagnosis of syncope (4) Is there evidence to suggest a high risk of cardiovascular events or . death (see section 4.1.2)? . The starting point of the diagnostic evaluation of TLOC of suspected . syncopal nature is the initial syncope evaluation, which consists of: TLOC has four specific characteristics: short duration, abnor- . . mal motor control, loss of responsiveness, and amnesia for . • Careful history taking concerning present and previous attacks, as the period of LOC (for an explanation of the clinical features of . well as eyewitness accounts, in person or through a telephone . interview. TLOC see Web Table 4 in section 4.1 of the Web Practical . . • Physical examination, including supine and standing BP Instructions). . . measurements. TLOC is probably syncope when: (i) there are signs and symptoms . . • Electrocardiogram (ECG). specific for reflex syncope, syncope due to OH, or cardiac syncope, . and (ii) signs and symptoms specific for other forms of TLOC (head . Based on these findings, additional examinations may be per- . formed when needed (see section 4.2): trauma, epileptic seizures, psychogenic TLOC, and/or rare causes) . are absent. Practical instructions for history taking are given in sec- . . • Immediate ECG monitoring when there is a suspicion of arrhyth- tions 3 and 4 of the Web Practical Instructions. . mic syncope. When epileptic seizures or psychogenic attacks are likely, appro- . . • Echocardiogram when there is previous known heart disease, priate steps should be taken. By using a detailed clinical history, phys- . data suggestive of structural heart disease, or syncope secondary icians can differentiate syncope from other forms of TLOC in . to cardiovascular cause.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 12 ESC Guidelines
• Carotid sinus massage (CSM) in patients aged >40 years. . Even if there is no independent gold/reference standard to diag- . • Head-up tilt testing when there is suspicion of syncope due to . nose syncope, there is strong consensus that the initial evalu- OH or reflex syncope. . ation may lead to certain or highly likely diagnosis when the . • Blood tests when clinically indicated, e.g. haematocrit or haemo- . diagnostic criteria listed in the table of recommendations are globin when haemorrhage is suspected, oxygen saturation and . met. blood gas analysis when hypoxia is suspected, troponin when car- . . diac ischaemia-related syncope is suspected, or D-dimer when . pulmonary embolism is suspected, etc. . .
Diagnostic criteria with initial evaluation
Recommendations Classa Levelb
Reflex syncope and OH
VVS is highly probable if syncope is precipitated by pain, fear, or standing, and is associated with typical progressive prodrome I C (pallor, sweating, and/or nausea).8,13–17
Situational reflex syncope is highly probable if syncope occurs during or immediately after specific triggers, listed in 13–17 I C Table 3.8,
Syncope due to OH is confirmed when syncope occurs while standing and there is concomitant significant OH.18–24 I C
In the absence of the above criteria, reflex syncope and OH should be considered likely when the features that suggest reflex IIa C syncope or OH are present and the features that suggest cardiac syncope are absent (see Table 5).
Cardiac syncope
Arrhythmic syncope is highly probable when the ECG shows25–39: • Persistent sinus bradycardia <40 b.p.m. or sinus pauses >3 s in awake state and in absence of physical training; • Mobitz II second- and third-degree AV block; • Alternating left and right BBB; I C • VT or rapid paroxysmal SVT; • Non-sustained episodes of polymorphic VT and long or short QT interval; or • Pacemaker or ICD malfunction with cardiac pauses.
Cardiac ischaemia-related syncope is confirmed when syncope presents with evidence of acute myocardial ischaemia with or I C without myocardial infarction.25–39
Syncope due to structural cardiopulmonary disorders is highly probable when syncope presents in patients with prolapsing I C atrial myxoma, left atrial ball thrombus, severe aortic stenosis, pulmonary embolus, or acute aortic dissection.
Additional advice and clinical perspectives The initial syncope evaluation, as described in this document, can define the cause of syncope in most patients. Strict adherence to the above defin- itions of VVS and situational reflex syncope, and of syncope due to OH, can be considered certain or highly likely irrespective of the presence of any other abnormal finding. In young subjects with unexplained syncope and no history of cardiac disease, no family history of sudden death, no su- pine syncope or syncope during sleep or exercise, no unusual triggers, and a normal ECG, the chance of cardiac syncope is very low. SCD rates in subjects <35 years amount to 1 – 3/100 000.
AV = atrioventricular; BBB = bundle branch block; b.p.m. = beats per minute; ECG = electrocardiogram; ICD = implantable cardioverter defibrillator; OH = orthostatic hypo- tension; SCD = sudden cardiac death; SVT = supraventricular tachycardia; VT = ventricular tachycardia; VVS = vasovagal syncope. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 13
. When a diagnosis is nearly certain or highly likely, no further evalu- . 4.1.2 Management of syncope in the emergency . ation is needed, and treatment—if any—can be planned. In other . department based on risk stratification cases, the initial evaluation may suggest a diagnosis when the features . The management of TLOC of suspected syncopal nature in the ED . listed in Table 5 are present, or otherwise is unable to suggest any . should answer the following three key questions: diagnosis. . . (1) Is there a serious underlying cause that can be identified? . . (2) What is the risk of a serious outcome? Table 5 Clinical features that can suggest a diagnosis . (3) Should the patient be admitted to hospital? on initial evaluation . . Figure 5 shows a flow chart for the management and risk stratifica- . Reflex syncope . tion of patients referred to the ED for TLOC suspected to be syn- Long history of recurrent syncope, in particular occurring be- . 40 • . cope (modified from Casagranda et al. ). fore the age of 40 years . . • After unpleasant sight, sound, smell, or pain . Question 1: Is there a serious underlying cause that can be • Prolonged standing . . identified in the ED? • During meal . Normally the presenting complaint of syncope can be established. • Being in crowded and/or hot places . . The primary aim for an ED clinician is then to establish an underlying • Autonomic activation before syncope: pallor, sweating, and/ . . diagnosis, especially those associated with the potential for rapid clin- or nausea/vomiting . . ical deterioration.41,42 It is the acute underlying disease that most fre- • With head rotation or pressure on carotid sinus (as in tu- . mours, shaving, tight collars) . quently determines short-term adverse events rather than the . 43 • Absence of heart disease . syncope itself. Subsequent management will focus on treating this . underlying cause (Figure 5). Many (40–45%) non-cardiovascular and Syncope due to OH . . some cardiovascular life-threatening underlying conditions are obvi- • While or after standing . . ous in the ED.44 Table 6 lists high-risk features that suggest the pres- • Prolonged standing . . ence of a serious underlying cause and low-risk features that suggest • Standing after exertion . • Post-prandial hypotension . a benign underlying cause. • Temporal relationship with start or changes of dosage of vas- . . odepressive drugs or diuretics leading to hypotension . Question 2: What is the risk of a serious outcome? • Presence of autonomic neuropathy or parkinsonism . High-risk features are shown in Table 6, and how to use this risk pro- . Cardiac syncope . file to guide subsequent management and disposition is shown in . Figure 6. • During exertion or when supine . Sudden onset palpitation immediately followed by syncope . Risk stratification is important, for two reasons: • . • Family history of unexplained sudden death at young age . • Presence of structural heart disease or coronary artery . (1) To recognize patients with a likely low-risk condition able to be dis- . charged with adequate patient education. disease . • ECG findings suggesting arrhythmic syncope: . (2) To recognize patients with a likely high-risk cardiovascular condition - Bifascicular block (defined as either left or right BBB com- . requiring urgent investigation. This may require admission. . bined with left anterior or left posterior fascicular block) . - Other intraventricular conduction abnormalities (QRS dur- . High-risk patients are more likely to have cardiac syncope. . 25–27,31,35,36,45 46 ation >_0.12 s) . Structural heart disease and primary electrical disease - Mobitz I second-degree AV block and 1 degree AV block . are major risk factors for sudden cardiac death (SCD) and overall . with markedly prolonged PR interval . mortality in patients with syncope. Low-risk patients are more likely - Asymptomatic mild inappropriate sinus bradycardia (40–50 . to have reflex syncope and have an excellent prognosis.47 OH is b.p.m.) or slow atrial fibrillation (40–50 b.p.m.) in the ab- . . associated with a two-fold higher risk of death owing to the severity sence of negatively chronotropic medications . . of comorbidities compared with the general population.48 - Non-sustained VT . - Pre-excited QRS complexes . . - Long or short QT intervals . Question 3: Should the patient be admitted to hospital? - Early repolarization . Approximately 50% of patients who present to the ED with - ST-segment elevation with type 1 morphology in leads . . syncope are admitted (although the rate varies between 12–86%) V1-V3 (Brugada pattern) . (see Supplementary Data Table 4). The use of clinical decision rules and - Negative T waves in right precordial leads, epsilon waves . . standardized protocols has not changed this rate significantly. The com- suggestive of ARVC . . posite estimate of outcomes is that in the next 7–30 days, only 0.8% - Left ventricular hypertrophy suggesting hypertrophic . cardiomyopathy . die and 6.9% have a non-fatal severe outcome whilst in the ED, while . another 3.6% have a post-ED serious outcome (see Supplementary . . Data Table 4). Unnecessary admission in low-risk patients can be harm- . ful.87 Whereas it is crucial to identify these high-risk patients to ensure ARVC = arrhythmogenic right ventricular cardiomyopathy; AV = atrioventricular; . BBB = bundle branch block; b.p.m. = beats per minute; ECG = electrocardio- . early, rapid, and intensive investigation, not all patients at high risk need gram; OH = orthostatic hypotension; VT = ventricular tachycardia. . hospitalization.80 .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 14 ESC Guidelines
Figure 5 The management of patients presenting to the emergency department for transient loss of consciousness suspected to be syncope (modified from Casagranda et al.40). ED = emergency department; TLOC = transient loss of consciousness. aFor example, this includes pulmonary embolism presenting with shortness of breath, pleuritic chest pain, and syncope, but not trauma secondary to syncope.
Management of syncope in the emergency department
Recommendations Classa Levelb
It is recommended that patients with low-risk features, likely to have reflex or situational syncope, or syncope due to OH, I B are discharged from the ED.27,35,36,49–54,58,62,69
It is recommended that patients with high-risk features receive an early intensive and prompt evaluation in a syncope unit or I B in an ED observation unit (if available), or are hospitalized.26,27,35,36,44–46,50,55–57,59,60,70–76
It is recommended that patients who have neither high- nor low-risk features are observed in the ED or in a syncope unit I B instead of being hospitalized.40,63–65,77
Risk stratification scores may be considered for risk stratification in the ED.78–86 IIb B
Additional advice and clinical perspectives • In the ED, presyncope should be managed with the same accuracy as syncope as it carries the same prognosis.66–68 • Diagnostic radiology and laboratory tests such as chest X-ray, brain computed tomography, routine blood haematology, biochemistry, and D-dimer and cardiac markers have a low diagnostic yield, impact on risk stratification of patients with syncope, and should not routinely be used unless specifically suggested by clinical evaluation. • Around 10% of patients with syncope in the ED will suffer from a serious outcome within 7–30 days of their visit, with just under half occurring after their stay in the ED (see Supplementary Data Table 4). It is crucial to identify these high-risk patients to ensure early, rapid, and intensive investigation. • As syncope units are both effective and efficient, this early, rapid, and intensive investigation can be performed on an outpatient basis (either in a syncope unit or an ED observation unit) in most cases. Only patients with a risk of a short-term serious outcome should be considered for hospital admission. • To reduce inappropriate admissions, patients who have a cardiac device and syncope should undergo prompt device interrogation. • Risk stratification scores perform no better than good clinical judgement and should not be used alone to perform risk stratification in the ED.
ED = emergency department; OH = orthostatic hypotension. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 15
Table 6 High-risk features (that suggest a serious condition) and low-risk features (that suggest a benign condition) in patients with syncope at initial evaluation in the emergency department
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 16 ESC Guidelines
AF = atrial fibrillation; ARVC = arrhythmogenic right ventricular cardiomyopathy; AV = atrioventricular; BP = blood pressure; b.p.m. = beats per minute; ECG = electrocardio- gram; ED = emergency department; ICD = implantable cardioverter defibrillator; LQTS = long QT syndrome; LVEF = left ventricular ejection fraction; SCD = sudden cardiac death; SVT = supraventricular tachycardia; VT = ventricular tachycardia. aSome ECG criteria are per se diagnostic of the cause of the syncope (see recommendations: Diagnostic criteria); in such circumstances appropriate therapy is indicated without further investigations. We strongly suggest the use of standardized criteria to identify ECG abnormalities with the aim of precise diagnosis of ECG-defined cardiac syndromes in ED practice.61
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 17
if
Figure 6 Emergency department risk stratification flow chart. Low- and high-risk features are listed in Table 6. ED = emergency department; SU = syncope unit. Patients with low-risk features. These patients do not need further diagnostic tests in the ED as they are likely to have reflex, situational, or orthostatic syncope. They may benefit from reassurance, or counselling (see Web Practical Instructions section 9.1: ESC information sheet for patients affected by reflex syncope). Patients with high-risk features. These patients should be classified as HIGH RISK; they require an intensive diagnostic approach and may need urgent treatment and admission. These patients should be monitored (although it is unclear for how long this should be, most studies suggesting up to 6 hours in the ED and up to 24 hours in hospital) in a setting where resuscitation can be performed in case of deterioration.40,62 Patients that have neither high- nor low-risk features. These patients will require expert syncope opinion, which can probably be safely man- aged in an outpatient setting.63 There is no direct evidence that admitting patients to hospital changes their outcome, whilst there is evi- dence that management in an ED observation unit and/or fast-track to a syncope outpatient unit is beneficial.64,65 aRecent studies have suggested that outcomes in patients presenting with presyncope are similar to those presenting with syncope.66–68 bThese patients may still require admission to hospital for associated illness, injury or welfare reasons. Low-risk patients can be referred to the outpatient syncope clinic for therapy purposes, if needed.
. The diagnostic tests, procedures, and interventions that may re- . <_48 h coupled with fast-tracking to a syncope unit reduced the ad- quire admission in patients with high-risk features are listed in Table 7. . mission rate to 29%.77 Among patients not admitted, 20% were dis- . Furthermore, this Task Force believes that the implementation . charged after a short observation in the ED, 20% were fast-tracked to of novel care pathways and organizational approaches, such as ED ob- . the syncope unit, and 31% were discharged directly from the ED.77 . servation units and syncope in- and outpatient units (Figure 6), . offer safe and effective alternatives to admission in the cases . Risk stratification scores: There are several ED syncope clinical 40 . listed in Table 7. Based on a consensus document, asingle-centre . decision rules that aim to stratify patients with syncope based on experience consisting of a short stay in the ED under observation of . medical history, examination, and ECG findings (see Supplementary .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 18 ESC Guidelines
Table 7 High-risk syncope patients: criteria favouring a stay in an emergency department observation unit and/or fast-tracking to a syncope unit vs. requiring admission to hospital
Favour initial management in ED observation unit and/or Favour admission to hospital fast-track to syncope unit
High-risk features AND: High-risk features AND: • Stable, known structural heart disease • Any potentially severe coexisting disease that requires admission • Severe chronic disease • Injury caused by syncope • Syncope during exertion • Need of further urgent evaluation and treatment if it cannot • Syncope while supine or sitting be achieved in another way (i.e. observation unit), e.g. ECG monitoring, • Syncope without prodrome echocardiography, stress test, electrophysiological study, angiography, • Palpitations at the time of syncope device malfunction, etc. • Inadequate sinus bradycardia or sinoatrial block • Need for treatment of syncope • Suspected device malfunction or inappropriate intervention • Pre-excited QRS complex • SVT or paroxysmal atrial fibrillation • ECG suggesting an inheritable arrhythmogenic disorders • ECG suggesting ARVC
ARVC = arrhythmogenic right ventricular cardiomyopathy; ECG = electrocardiogram; ED = emergency department; SVT = supraventricular tachycardia.
26,34–36,44,88 . Data Table 3). None of these rules are used widely in EDs . syndrome (CSS) requires the reproduction of spontaneous symp- due to poor sensitivity and specificity reported from external valida- . toms and, in addition, that patients have syncope of unknown ori- 70,78–85 . tion, or due to a lack of external validation. Syncope clinical . gin compatible with a reflex mechanism. In such circumstances, decision rules perform no better than clinician judgment at predicting . CSM usually shows a period of asystole >6 s.91 Theprevalenceof 86 . short-term serious outcomes. Clinical decision rules can predict . CSS, as defined here, was 8.8% when CSM was performed after poor outcomes, but most syncope deaths and many poor outcomes . the initial evaluation in 1855 consecutive patients >40 years of 58 . 92,93 are associated with underlying illness rather than syncope per se, . age with syncope compatible with a reflex mechanism. In a particularly in the long term.56 . multicentre study94 aimed at validation of the 2009 ESC . . Guidelines, CSM was indicated after initial evaluation in 73% of Even if the quality of evidence is moderate, there is strong con- . 700 patients and was diagnostic in 12%. The precise methodology . sensus from several studies that currently available risk stratifi- . andresultsofCSMareshowninsection5oftheWeb Practical cation scores have not shown better sensitivity, specificity, or . Instructions. . prognostic yield compared with clinical judgment in predicting . The main complications of CSM are neurological. When pooling . 90,95–97 short-term serious outcomes after syncope. Therefore, they . the data from four studies in which 8720 patients were ana- should not be used alone to perform risk stratification in . lysed, TIAs or strokes were observed in 21 (0.24%). . the ED. . The relationship between abnormal response to CSM and . spontaneous syncope is a crucial point that has been studied using . 4.2 Diagnostic tests . two methods. The first was a pre-post comparison of the recur- . 4.2.1 Carotid sinus massage . rence rate of syncope after pacing. Non-randomized studies dem- . onstrated fewer recurrences at follow-up in paced patients than in A ventricular pause lasting >3 s and/or a fall in systolic BP of >50 . mmHg is known as carotid sinus hypersensitivity. Carotid sinus . those without pacing. These results were confirmed in two . 98,99 hypersensitivity is a common finding in older men without syn- . randomized trials. Thesecondmethodwastoanalysethe cope; abnormal responses are frequently observed (<_40%) in . occurrence of asystolic episodes registered in patients with a car- . patients without syncope, especially if they are older and affected . dioinhibitory response to CSM using an implanted device. 89 . by cardiovascular disease. Carotid sinus hypersensitivity is . Recordings of long pauses were very common in the two trials 90 . 100,101 exceptional in patients <40 years of age. The specificity of the . that employed this method. These results suggest that a test increases if spontaneous syncope is reproduced during CSM. . positive response to CSM, reproducing symptoms, in patients . Syncope was induced in only 5% of asymptomatic persons aged . with syncope is highly predictive of the occurrence of spontane- >65 years.89 For the above reasons, the diagnosis of carotid sinus . ous asystolic episodes.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 19
There is strong consensus that the diagnosis of CSS requires . neous events, and indirectly by studies of efficacy of cardiac . . pacing. Further research is likely to have an important impact both the reproduction of spontaneous symptoms during CSM . and clinical features of spontaneous syncope compatible with . on our confidence in the estimation of effect and may change . a reflex mechanism. The quality of evidence is moderate and is . the estimate. given by studies of ECG correlation between CSM and sponta- .
Cardiac sinus massage
Recommendations Classa Levelb
Indications
CSM is indicated in patients >40 years of age with syncope of unknown origin compatible with a reflex mechanism.92–94 I B
Diagnostic criteria
CSS is confirmed if CSM causes bradycardia (asystole) and/or hypotension that reproduce spontaneous symptoms, and I B patients have clinical features compatible with a reflex mechanism of syncope.89,90,92,93,98–102
Additional advice and clinical perspectives • History of syncope and its reproduction by CSM defines CSS; positive CSM without a history of syncope defines carotid sinus hypersensitiv- ity.89,90,92,93 Carotid sinus hypersensitivity in patients with unexplained syncope may be a non-specific finding because it is present in <_40% of older populations and should be used with caution for diagnosis of the mechanism of syncope. • CSM should be performed with the patient in the supine and upright positions, and with continuous beat-to-beat BP monitoring. This may be more readily performed in the tilt laboratory.90 • Although neurological complications are very rare,90,95–97 the risk of provocation of TIA with the massage suggests that CSM should be under- taken with caution in patients with previous TIA, stroke, or known carotid stenosis >70%.
BP = blood pressure; CSM = carotid sinus massage; CSS = carotid sinus syndrome; TIA = transient ischaemic attack. aClass of recommendation. bLevel of evidence.
. . a disadvantage due to the rapidly falling BP during OH. With a sphyg- 4.2.2 Orthostatic challenge . Changing from the supine to the upright position produces a dis- . momanometer, more than four measurements per minute cannot . placement of blood from the thorax to the lower limbs and abdomi- . be obtained without venous obstruction in the arm. When more fre- nal cavity that leads to a decrease in venous return and cardiac . quent readings are required, as for initial OH, continuous beat-to- . 20,103,104 output. In the absence of compensatory mechanisms, a fall in BP may . beat non-invasive BP measurement is needed. lead to syncope.20,103,104 The diagnostic criteria for OH have been . 6 . defined by consensus. . Diagnostic criteria: Abnormal BP fall is defined as a progressive Currently, there are three methods for assessing the response to . and sustained fall in systolic BP from baseline value >_20 mmHg or 20,103,104 . change in posture from supine to erect : active standing (see . diastolic BP >_10mmHg,oradecreaseinsystolicBPto<90 section 4.2.2.1), head-up tilt (see section 4.2.2.2), and 24-h ambula- . mmHg. This definition of OH differs from the 2011 consensus6 in . tory BP monitoring (ABPM) (see section 4.2.3.4). . adding the 90 mmHg threshold. This Task Force believes that an . absolute threshold of 90 mmHg of systolic BP is useful, especially . 4.2.2.1 Active standing . in patients with a supine BP <110 mmHg. An isolated diastolic BP . drop is very rare and its clinical relevance for OH diagnosis is lim- . Indications: This test is used to diagnose different types of ortho- . ited. Orthostatic heart rate (HR) increase is blunted or absent static intolerance (see Web Practical Instructions Web Table 1). A . [usually not >10 beats per minute (b.p.m.)] in patients with neuro- . sphygmomanometer is adequate for routine clinical testing for classi- . genic OH, but increases or even exaggerates with anaemia or cal OH and delayed OH because of its ubiquity and simplicity. . hypovolaemia. The probability that syncope and orthostatic com- . Automatic arm-cuff devices, which are programmed to repeat and . plaints are due to OH can be assessed using the information given confirm measurements when discrepant values are recorded, are at . in Table 8. .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 20 ESC Guidelines
Table 8 Association of orthostatic intolerance and orthostatic hypotension
History of syncope and orthostatic complaints
Highly suggestive of OH: syncope and pre- Possibly due to OH: not all of the features syncope are present during standing, absent highly suggestive of OH are present while lying, and less severe or absent while sit- ting; a predilection for the morning; sitting or lying down must help; complaints may get worse immediately after exercise, after meals or in high temperatures; no “autonomic activation”
Supine and standing Symptomatic abnormal BP fall Syncope is due to OH (Class I) Syncope is likely due to OH (Class IIa) BP measurement Asymptomatic abnormal BP fall Syncope is likely due to OH (Class IIa) Syncope may be due to OH (Class IIb)
No abnormal BP drop Unproven Unproven
BP = blood pressure; OH = orthostatic hypotension.
Active standing
Recommendations Classa Levelb
Indications
Intermittent determination by sphygmomanometer of BP and HR while supine and during active standing for 3 min are indi- I C cated at initial syncope evaluation.20,103,104
Continuous beat-to-beat non-invasive BP and HR measurement may be preferred when short-lived BP variations are sus- IIb C pected, such as in initial OH.20,103,104
Diagnostic criteria
Syncope due to OH is confirmed when there is a fall in systolic BP from baseline value >_20 mmHg or diastolic BP >_10 I C mmHg, or a decrease in systolic BP to <90 mmHg that reproduces spontaneous symptoms.6,20,103,104
Syncope due to OH should be considered likely when there is an asymptomatic fall in systolic BP from baseline value >_20 mmHg or diastolic BP >_10 mmHg, or a decrease in systolic BP to <90 mmHg, and symptoms (from history) are consistent IIa C with OH.6,20,103,104
Syncope due to OH should be considered likely when there is a symptomatic fall in systolic BP from baseline value >_20 mmHg or diastolic BP >_10 mmHg, or a decrease in systolic BP to <90 mmHg, and not all of the features (from history) are IIa C suggestive of OH.6,20,103,104
POTS should be considered likely when there is an orthostatic HR increase (>30 b.p.m. or to >120 b.p.m. within 10 min of IIa C active standing) in the absence of OH that reproduces spontaneous symptoms.6,20,103,104
Syncope due to OH may be considered possible when there is an asymptomatic fall in systolic BP from baseline value >_20 mmHg or diastolic BP >_10 mmHg, or a decrease in systolic BP to <90 mmHg, and symptoms (from history) are less consis- IIb C tent with OH.6,20,103,104
BP = blood pressure; b.p.m. = beats per min; OH = orthostatic hypotension; HR = heart rate; POTS = postural orthostatic tachycardia syndrome. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 21
. 4.2.2.2 Tilt testing . considered: (i) to confirm a diagnosis of reflex syncope in patients in Since its introduction in 1986,105 many protocols have been reported . whom this diagnosis was suspected but not confirmed by initial eval- . 105–109,111 with variations in the initial stabilization phase, duration, tilt angle, . uation , and (ii) for the assessment of autonomic type of support, and pharmacological provocation. The most com- . failure, especially for the reproduction of delayed OH (which could not . 23,24,112,113 monly used are the trinitroglycerin (TNG) test using 300–400 mgof . be detected by active standing because of its delayed onset) sublingual TNG after a 20-min unmedicated phase,106,107 and the . and postural orthostatic tachycardia syndrome (POTS).114 Tilt testing . 115–117 low-dose intravenous isoproterenol test, which uses incremental . may be helpful in separating syncope from PPS. . 118 doses to increase average HR by about 20–25% over baseline (usu- . Tilt testing has limited value in assessing treatment efficacy. 108,109 110 . ally <_3 mg/min). In a recent systematic literature review, the . However, tilt testing is widely accepted as a useful tool to demon- overall positivity rate in patients with syncope was 66% for the TNG . strate susceptibility of the patient to reflex syncope, especially a . protocol and 61% for the isoproterenol protocol; the respective pos- . hypotensive (vasodepressive) tendency, and thereby to initiate treat- itivity rate in subjects without syncope (controls) ranged from . ment (e.g. physical manoeuvres, see section 5).119–121 . 11–14%; and the test differentiated patients with syncope from con- . The endpoint of tilt testing is the reproduction of trols with an odds ratio of 12. The methodology and classification of . symptoms along with the characteristic circulatory pattern of . responses are described in section 6 of the Web Practical Instructions. . the indication mentioned above, namely the induction of reflex hypo- Adding video recording to a tilt table permits objective and repeated . tension/bradycardia, OH, POTS, or PPS. The typical tilt test result . review of clinical signs in relation to BP and HR, and helps to assess . patterns are shown in the Web Practical Instructions section 6. . the relative contribution of bradycardia and hypotension to syncope . (see section 5.2.6.3 and the explanatory video in Web Practical . Interpretation of tilt testing results in patients with reflex syncope: . 122,123 Instructions section 6.3.15), and to distinguish between VVS and PPS . Some studies compared the response to tilt testing with sponta- (see section 4.2.5). . neous syncope recorded by an implantable loop recorder (ILR). While . The clinical situation corresponding to tilt-induced syncope is that . a positive cardioinhibitory response to tilt testing predicts, with a high which is triggered by prolonged standing. The test should be . probability, an asystolic spontaneous syncope, the presence of a
Tilt testing
Recommendations Classa Levelb
Indications
Tilt testing should be considered in patients with suspected reflex syncope, OH, POTS, or PPS.23,24,105–109,111–117 IIa B
Tilt testing may be considered to educate patients to recognize symptoms and learn physical manoeuvres.119–121 IIb B
Diagnostic criteria
Reflex syncope, OH, POTS, or PPS should be considered likely if tilt testing reproduces symptoms along with the charac- IIa B teristic circulatory pattern of these conditions.23,24,105–109,111–117
Additional advice and clinical perspectives • A negative tilt table response does not exclude a diagnosis of reflex syncope. • While sensitivity and specificity are at acceptable levels when measured in patients with VVS and healthy controls, in usual clinical settings of syncope of uncertain origin tilt testing suggests the presence of a hypotensive susceptibility, which may exist not only in reflex syncope but also with other causes of syncope including some forms of cardiac syncope. The concept of hypotensive susceptibility rather than diagnosis has important practical utility, because the presence or absence of hypotensive susceptibility plays a major role in guiding pacemaker therapy in patients affected by reflex syncope and in the management of hypotensive therapies, which are frequently present in the elderly with syncope (see sections 5.1 and 5.2). • A positive cardioinhibitory response to tilt testing predicts, with high probability, asystolic spontaneous syncope; this finding is relevant for thera- peutic implications when cardiac pacing is considered (see section 5.2.6). Conversely, the presence of a positive vasodepressor, a mixed response, or even a negative response does not exclude the presence of asystole during spontaneous syncope.122,123 • Tilt testing may be helpful in separating syncope with abnormal movements from epilepsy.137 • Tilt testing may have value in distinguishing syncope from falls.23 • Tilt testing may be helpful in separating syncope from PPS. In suspected PPS, the tilt test should preferably be performed together with EEG mon- itoring; a normal EEG helps to confirm the diagnosis.116,117 In the absence of an EEG, a video recording will be helpful in confirming the diagnosis. • Tilt testing should not be used to assess the efficacy of a drug treatment.118
EEG = electroencephalogram; OH = orthostatic hypotension; POTS = postural orthostatic tachycardia syndrome; PPS = psychogenic pseudosyncope; VVS = vasovagal syncope. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 22 ESC Guidelines
. . VVS. This concept has practical implications for therapy (see sec- . . tions 5.1 and 5.2). . . . . 4.2.3 Basic autonomic function tests . . Autonomic function assessment helps to identify autonomic failure as . the underlying cause of syncope. . . . 4.2.3.1 Valsalva manoeuvre . . The methodology of the Valsalva manoeuvre is described in section . 7.1.1 of the Web Practical Instructions and in Web Video 2. There is . . strong evidence that the absence of a BP overshoot and an absence . of a HR increase during the Valsalva is pathognomonic for neurogenic . . OH, occurring in primary and secondary autonomic failure, and the . degree of hypotension and/or lack of compensation during forced . . expiration usually correlate with the degree of autonomic dysfunc- . tion and related symptoms.138–143 In contrast, a pronounced BP fall . . beyond what is normally expected during forced expiration, but a . . normal chronotropic response during the manoeuvre, may occur in . patients with suspected situational syncope, i.e. syncope occurring . Figure 7 Rates of tilt testing positivity in different clinical condi- . during some forms of situational syncope, e.g. coughing, brass instru- tions. These studies used the Westminster protocol for passive . ment playing, singing, and weightlifting.144 125 106 . tilt, the Italian protocol for trinitroglycerin tilt, and the clo- . mipramine protocol,124 for a total of 1453 syncope patients and . . 4.2.3.2 Deep breathing 407 controls without syncope. Studies using other tilt protocols, . The methodology of the deep-breathing test is described in section e.g. isoproterenol challenge, were not included. Clom = clomipr- . . 7.1.2 of the Web Practical Instructions. Under physiological conditions, amine; TNG = trinitroglycerin; VVS = vasovagal syncope. . . HR rises during inspiration and falls during expiration. HR variability . during deep breathing (also called the expiratory/inspiratory index or . 145 . E/I index) is >_15 b.p.m. in healthy individuals aged >50 years. positive vasodepressor, mixed response, or even a negative response, . . There is strong consensus that blunted or abolished variation is sug- . 142,143,146,147 does not exclude the presence of asystole during spontaneous . gestive of parasympathetic dysfunction. syncope.122,123 . 124 . Tilt testing has an acceptable sensitivity and specific- . 4.2.3.3 Other autonomic function tests 106,124,125 . ity when these are calculated in patients with true VVS . Further tests to evaluate cardiovascular sympathetic function include or without a history of syncope. However, there is an inability to . calculation of the 30:15 ratio, the cold pressure test, the sustained . apply the test to populations with syncope of uncertain cause . hand grip test, and mental arithmetic. There is weak evidence that where it is hoped that tilt testing might prove decisive. In these . these tests may be useful.13,142,143,147 . clinical settings, tilt testing fails to deliver (Figure 7). Indeed, tilt . testing was positive in 51–56% of patients with atypical clinical fea- . 4.2.3.4 Twenty-four-hour ambulatory and home blood pressure 106,124–128 . tures suggesting a reflex mechanism, in 30–36% with . monitoring 124,129 . unexplained syncope after full investigation, and in 45–47% . Twenty-four-hour ABPM and home BP monitoring (HBPM) are 130,131 . with true cardiac arrhythmic syncope. In other words, tilt . increasingly used to diagnose and monitor the treatment of hyperten- testing offers little diagnostic value in patients for whom it is most . 148 . sion. There is strong evidence that OH is frequently associated with needed. In these patients, a positive tilt test reveals a susceptibility . a nocturnal ‘non-dipping’ or even ‘reverse-dipping’ BP pattern in 132 . to orthostatic stress. This hypotensive susceptibility plays a role in . patients with autonomic failure, with relevant therapeutic and prognos- causing syncope irrespective of the aetiology and mechanism of . 140,148–151 . tic implications (see Web Practical Instructions section 7.1.3). In syncope. For example, in arrhythmic syncope caused by paroxys- . these patients, ABPM allows the assessment of nocturnal hypertension, mal atrial tachyarrhythmias, the mechanism is a combination of . . postprandial hypotension, and exercise- and drug-induced hypoten- onset of the arrhythmia itself and hypotensive susceptibility, . sion, as well as monitoring for side effects of antihypotensive regimens corroborated by positive tilt testing.130,131 Similarly, multifactorial . 152 . and pointing to additional disorders such as sleep apnoea. There is mechanisms are likely in other types of cardiac syncope, e.g. aortic . weak evidence that ABPM may also detect the degree of OH in daily 133 134 . stenosis, hypertrophic cardiomyopathy (HCM), and . life better than single office BP measurements.153 135,136 . sick sinus syndrome. The presence or absence of suscepti- . HBPM may be used to investigate the cause of orthostatic intoler- . bility explains the occurrence of syncope in some and not in . ance, i.e. to clarify whether symptoms are due to OH or to other others affected by the same severity of arrhythmia or structural . causes, such as vertigo or motor imbalance in Parkinson’s disease or . defect. Tilt testing should now be considered a means of . multiple system atrophy. The evidence is weak. Finally, HBPM can be exposing a hypotensive tendency rather than being diagnostic of . used to clarify that BP is not low during episodes of PPS.154
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 23
Basic autonomic function tests
Recommendations Classa Levelb
Valsalva manoeuvre
Valsalva manoeuvre should be considered for the assessment of autonomic function in patients with suspected neurogenic IIa B OH.138–143
Valsalva manoeuvre may be considered for confirming the hypotensive tendency induced by some forms of situational syn- IIb C cope, e.g. coughing, brass instrument playing, singing, and weightlifting.144
Deep-breathing test
Deep-breathing tests should be considered for the assessment of autonomic function in patients with suspected neurogenic IIa B OH.142,143,146,147
Other autonomic function tests
Other autonomic function tests (30:15 ratio, cold pressure test, sustained hand grip test, and mental arithmetic test) may IIb C be considered for the assessment of autonomic function in patients with suspected neurogenic OH.13,142,143,147
ABPM
ABPM is recommended to detect nocturnal hypertension in patients with autonomic failure.140,148–151 I B
ABPM should be considered to detect and monitor the degree of OH and supine hypertension in daily life in patients with IIa C autonomic failure.152,153
ABPM and HBPM may be considered to detect whether BP is abnormally low during episodes suggestive of orthostatic IIb C intolerance.
Additional advice and clinical perspectives • Whenever possible, reproduction of the trigger situation (e.g. coughing, swallowing, laughing, bass instrument playing, weightlifting) under beat- to-beat non-invasive HR and BP measurement should be performed in patients with suspected situational syncope. • The effects of age and sex should be considered when interpreting autonomic function tests.145,155–157 • Compliance with autonomic function tests may be limited in patients with dementia. Patients with tremor or Parkinsonism may not succeed in performing the sustained hand grip test. The cold pressure test may be uncomfortable in patients with Raynaud’s phenomena.147
ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HBPM = home blood pressure monitoring; HR = heart rate; OH = orthostatic hypotension. aClass of recommendation. bLevel of evidence.
4.2.4 Electrocardiographic monitoring (non-invasive and . 4.2.4.2 Holter monitoring . invasive) . Since, in most patients, symptoms do not recur during monitoring, the The role of ECG monitoring cannot be defined in isolation. As a rule, . true yield of Holter monitoring in syncope may be as low as 1–2% in . ECG monitoring is indicated only when there is a high pre-test proba- . an unselected population. In 15% of patients, symptoms were not asso- . 161 bility of identifying an arrhythmia associated with syncope, such as . ciated with arrhythmia. Thus, in these patients, a rhythm disturbance those listed in Table 5. . could potentially be excluded as a cause of syncope. Holter monitoring . . in syncope is inexpensive in terms of set-up costs, but expensive in . 162 4.2.4.1 In-hospital monitoring . terms of cost per diagnosis. Holter monitoring in syncope may be of . more value if symptoms are frequent. Daily single or multiple episodes In-hospital monitoring (in bed or by telemetry) is warranted in . patients with high-risk clinical features (defined in Table 6) suggesting . of LOC might increase the potential for symptom–ECG correlation. . arrhythmic syncope, especially if the monitoring is applied immedi- . ately after syncope. Although the diagnostic yield of ECG monitoring . 4.2.4.3 Prospective external event recorders 158–160 . varies from 1.9–17.6%, it is justified by the need to avoid . Event recorders are external devices that are applied by the patient immediate risk to the patient. . when symptoms occur. Whereas these recorders can be useful in .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 24 ESC Guidelines
. the investigation of palpitations,163 they have a marginal role in the . There are several areas of interest other than unexplained syn- . evaluation of syncope. . cope in which ILRs have been investigated: . . Patients with bundle branch block (BBB) in whom paroxysmal 4.2.4.4 Smartphone applications . • . atrioventricular (AV) block is likely despite negative complete Because up to now smartphone applications have recorded real-time . . EPS: an arrhythmia was observed in 41% of these patients (being ECG, their current role in syncope is limited for the same reason as . paroxysmal AV block in 70%) under ILR observation, based on 164,165 . for prospective event recorders. However, home video . pooled data from three studies174,187,188 (see Supplementary Data records are very useful in all forms of TLOC (see section 4.2.5.2). . . Table 6). . • Patients in whom epilepsy was suspected but the treatment has 4.2.4.5 External loop recorders . proven ineffective: in pooled data, an attack could have . In general, external loop recorders have a higher diagnostic yield than . been documented by ILR in 62% of patients, with an arrhythmic 162 . 137,189–191 Holter monitoring. External loop recorders can be useful in . cause being responsible in 26% (see Supplementary Data 166–168 . patients with relatively frequent syncope episodes. In a recent . Table 7). . Patients with unexplained falls: in pooled data, an attack could multicentre international registry, the diagnostic yield in syncope was . • . have been documented by ILR in 70% of patients, with an 24.5%, with the most common finding being bradyarrhythmias; the . 191–194 . arrhythmic cause being responsible in 14% (see stronger predictor for diagnostic findings was early monitoring after . Supplementary Data Table 8). 166 . the index event. . Patients with HCM, arrhythmogenic right ventricular cardiomy- . • . opathy (ARVC), or primary electrical diseases (see section 5.4). 4.2.4.6 Remote (at home) telemetry . . Most recently, external and implantable device systems have been . 4.2.4.8 Diagnostic criteria developed that provide continuous ECG recording or 24-h loop . The gold standard for the diagnosis of arrhythmic syncope is when . memory with wireless transmission (real time) to a service centre. . there is a correlation between the symptoms and an ECG record- Some recent studies have shown that implementing remote monitor- . ing.195,196 The presence of asymptomatic significant arrhythmias— . ing increases the diagnostic yield and achieves diagnosis earlier than . defined as prolonged asystole (>_3 s), rapid supraventricular 169–171 . without remote monitoring. . tachycardias (SVTs) (i.e. >160 b.p.m. for >32 beats), or ventricular . . tachycardias (VTs)—has been considered by several authors to be a 4.2.4.7 Implantable loop recorders . diagnostic finding.185,188,197–199 On the other hand, although the In a meta-analysis of five randomized controlled trials (RCTs),172–176 . . absence of documentation of an arrhythmia during a syncopal epi- 660 patients with unexplained syncope were randomized to a con- . sode cannot be considered to be a specific diagnosis, it allows the ventional strategy consisting of an external loop recorder, tilt testing, . . exclusion of an arrhythmia as the mechanism of the syncope. Most and an electrophysiological study (EPS), or to prolonged monitoring . evidence in support of the above diagnostic criteria is indirectly based with an ILR. The results showed that initial implantation of an ILR in . . on the benefit of specific therapies guided by ECG monitoring in pre- the workup provided a 3.7 [95% confidence interval (CI) 2.7–5.0] . venting syncopal recurrences.172,184–186,188,200 increased relative probability of a diagnosis compared with the con- . . Even if the quality of evidence is moderate, there is strong con- ventional strategy (see Supplementary Data Table 5). ILR was more . sensus based on evidence from several controlled trials that a 172,173,177,178 . cost-effective than a conventional strategy. . correlation between symptoms and a documented arrhythmia, 179 . In pooled data from nine studies performed in 506 patients with . or the presence of some asymptomatic significant arrhythmias unexplained syncope at the end of complete negative work-up, a cor- . (defined above), is diagnostic of the cause of syncope and spe- . relation between syncope and ECG was found in 176 patients (35%); . cific treatment must be prescribed. of these, 56% had asystole (or bradycardia in a few cases) at the time . . The principal limitation of any ECG monitoring device is the of the recorded event, 11% had tachycardia, and 33% had no arrhyth- . . inability to record BP together with ECG. In reflex syncope, the mia. Presyncope was much less likely to be associated with an . . documentation of bradycardia/asystole during a syncopal episode arrhythmia than syncope. Similar findings were subsequently . . does not rule out the possibility that a hidden hypotensive reflex observed with ILR use expanded in an early phase of evaluation in . . is the principal cause for syncope, and that bradycardia/asystole is patients with recurrent syncope of uncertain origin, in the absence of . . a secondary late event. This issue has important implications for high-risk criteria and structural heart disease,176,180–183 and in sus- . . therapy (see section 5). A classification of ECG recordings with pected reflex syncope.184–186 In particular, an asystolic pause was . . their probable related pathophysiology is available in Web Table 6 present during syncope in about 50% of these patients. . . and Web Practical Instructions section 8. .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 25
Electrocardiographic monitoring
Recommendations Classa Levelb
Indications
Immediate in-hospital monitoring (in bed or by telemetry) is indicated in high-risk patients (defined in Table 6). I C
Holter monitoring should be considered in patients who have frequent syncope or presyncope (>_1 episode per week).161 IIa B
External loop recorders should be considered, early after the index event, in patients who have an inter-symptom interval <_4 IIa B weeks.162,166,168,201
ILR is indicated in an early phase of evaluation in patients with recurrent syncope of uncertain origin, absence of high-risk criteria (listed in Table 6), and a high likelihood of recurrence within the battery life of the device.175,176,181–184,202, I A Supplementary Data Table 5
ILR is indicated in patients with high-risk criteria (listed in Table 6) in whom a comprehensive evaluation did not demon- strate a cause of syncope or lead to a specific treatment, and who do not have conventional indications for primary preven- I A tion ICD or pacemaker indication.174,180,187,188,195, Supplementary Data Tables 5 and 6
ILR should be considered in patients with suspected or certain reflex syncope presenting with frequent or severe syncopal IIa B episodes.184–186
ILR may be considered in patients in whom epilepsy was suspected but the treatment has proven ineffective.137,189–191, IIb B Supplementary Data Table 7
ILR may be considered in patients with unexplained falls.191–194, Supplementary Data Table 8 IIb B
Diagnostic criteria
Arrhythmic syncope is confirmed when a correlation between syncope and an arrhythmia (bradyarrhythmia or tachyar- I B rhythmia) is detected.172,184–186,188,200
In the absence of syncope, arrhythmic syncope should be considered likely when periods of Mobitz II second- or third- degree AV block or a ventricular pause >3 s (with the possible exception of young trained persons, during sleep or rate- IIa C controlled atrial fibrillation), or rapid prolonged paroxysmal SVT or VT are detected.185,188,197–199
Additional advice and clinical perspectives • Be aware that the pre-test selection of the patients influences the subsequent findings. Include patients with a high likelihood of arrhythmic events. The duration (and technology) of monitoring should be selected according to the risk and the predicted recurrence rate of syncope.158–160,183 • Exclude patients with a clear indication for ICD, pacemaker, or other treatments independent of a definite diagnosis of the cause of syncope. • Include patients with a high probability of recurrence of syncope in a reasonable time. Owing to the unpredictability of syncope recurrence, be prepared to wait up to 4 years or more before obtaining such a correlation.203 • In the absence of a documented arrhythmia, presyncope cannot be considered a surrogate for syncope, whereas the documentation of a signifi- cant arrhythmia at the time of presyncope can be considered a diagnostic finding.199 • The absence of arrhythmia during syncope excludes arrhythmic syncope.
AV = atrioventricular; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; SVT = supraventricular tachycardia; VT = ventricular tachycardia. aClass of recommendation. bLevel of evidence.
. 4.2.5 Video recording in suspected syncope . relation to BP and HR objectively and repeatedly, thus helping to dis- 4.2.5.1 In-hospital video recording . tinguish VVS from PPS. This approach has revealed new pathophysio- . 9 For PNES, a video-electroencephalogram (EEG) forms the highest . logical insights in syncope. Attaching the camera to the tilt table level of diagnostic probability.204 For syncope and PPS, video can play . allows detailed study of the face and head, which is useful when . 9,205 a similar, probably underused, role (see section 7). Adding video . assessing the start and end of LOC. Video recording of tilt- recording to a tilt table test adds the ability to review clinical signs in . induced PPS116 ensures that apparent TLOC occurs while BP and HR .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 26 ESC Guidelines
. are not low; adding an EEG increases the diagnostic probability of . sinoatrial block, usually documented by 12-lead ECG or ECG moni- . PPS even further. The method has been proven to show the com- . toring. The prognostic value of a prolonged sinus node recovery time bined presence of VVS and PPS.117 . (SNRT) is not well defined. An abnormal response is defined as >_1.6 . 210 . or 2 s for SNRT, or >_525 ms for corrected SNRT. One observatio- 4.2.5.2 Home video recording . nal study showed a relationship between the presence of prolonged . 211 Home video records (by means of smartphone technology) are very . SNRT at EPS and the effect of pacing on symptoms. Another small useful in all forms of TLOC to allow signs of an attack to be studied. . prospective study showed that a corrected SNRT >_800 ms had an . 212 Patients and their relatives should be urged to record attacks, if possi- . eight-fold higher risk of syncope than a SNRT below this value. ble, in cases of diagnostic uncertainty. In epilepsy, advances are made . . towards prolonged video and EEG recording in patients’ . 4.2.6.2 Syncope in bifascicular bundle branch block (impending high- homes.206,207 For syncope or PPS, experience suggests that the chan- . degree atrioventricular block) . ces of obtaining a video record are higher for PPS than for syncope, . Patients with bifascicular block and syncope are at higher risk of devel- . 213 which is probably the effect of a high frequency and long duration of . oping high-degree AV block. A prolonged HV interval >_70 ms, or attacks in PPS. It is rare for the beginning of events to be recorded.206 . induction of second- or third-degree AV block by pacing or by phar- . Home video records allow complex events such as syncope-induced . macological stress (ajmaline, procainamide, or disopyramide), identi- 208 . epileptic seizures to be diagnosed. . fies a group at higher risk of developing AV block. By combining the . above-mentioned parts of the electrophysiological protocol, a positive . . EPS yielded a positive predictive value as high as >_80% for the identifi- . 214–216 Video recording in suspected syncope . cation of patients who will develop AV block in old studies. . This finding has been indirectly confirmed by recent studies that . a b . showed a significant reduction in syncopal recurrences in patients Recommendations Class Level . . with prolonged HV implanted with a pacemaker compared with a Home video recordings of spontaneous . 188 . control group of untreated patients with a negative EPS ,orwitha events should be considered. Physicians . control group who received an empiric pacemaker.217 These results should encourage patients and their rel- IIa C . . justifyanupgradeoftherecommendationforEPS-guidedtherapy(i.e. atives to obtain home video recordings . cardiac pacing) in patients with a positive EPS from class IIa to class I. of spontaneous events.206,208 . . . Even if the quality of evidence is moderate, there is strong con- Adding video recording to tilt testing . may be considered in order to increase . sensus that a positive EPS indicates that the likely mechanism IIb C . the reliability of clinical observation of . of syncope is paroxysmal AV block. 9,116,117,205 . Conversely, approximately one-third of patients with a negative EPS in induced events. . . whom an ILR was implanted developed intermittent or permanent AV . block on follow-up.187 Thus, EPS has a low negative predictive value. aClass of recommendation. . b . Level of evidence. . Mortality is high in patients with syncope and BBB. However, neither . . syncope nor prolonged H-V interval were associated with a higher risk . 213 . of death, and pacemaker therapy did not decrease this risk. . . 4.2.6 Electrophysiological study . 4.2.6.3 Suspected tachycardia . In patients with syncope preceded by a sudden onset of brief palpita- . Indications: In an overview of eight studies, including 625 patients . tions suggesting SVT or VT, an EPS may be indicated to assess the with syncope undergoing EPS,209 positive results occurred predomi- . exact mechanism, especially when a curative catheter ablation proce- . nantly in patients with structural heart disease. In recent years, the . dure is considered to be beneficial. development of powerful non-invasive methods, i.e. prolonged ECG . In patients with a previous myocardial infarction and preserved left . monitoring, showing a higher diagnostic value, has decreased the . ventricular ejection fraction (LVEF), induction of sustained mono- . 218 importance of EPS as a diagnostic test. In clinical practice, registry data . morphic VT is strongly predictive of the cause of syncope, show that approximately 3% of patients with unexplained syncope . . whereas the induction of ventricular fibrillation (VF) is considered a evaluated by cardiologists undergo EPS and even fewer if they are . non-specific finding.37 The absence of induction of ventricular 71 . 219 evaluated by other specialists. Nevertheless, EPS remains useful for . arrhythmias identifies a group at lower risk of arrhythmic syncope. diagnosis in the following specific clinical situations: asymptomatic . The role of EPS and the use of pharmacological challenge by . sinus bradycardia (suspected sinus arrest causing syncope), bifascicu- . class I antiarrhythmic drugs in patients with syncope and sus- lar BBB (impending high-degree AV block), and suspected . pected Brugada syndrome is controversial. In a recent meta-analy- . 220 tachycardia. . sis, the risk of arrhythmic events was slightly increased in . patients with a history of unexplained syncope or a spontaneous . Diagnostic criteria: 4.2.6.1 Asymptomatic sinus bradycardia: sus- . type 1 pattern, and who had induction of VT or VF with one or pected sinus arrest causing syncope . two extra stimuli. However, the absence of induction in such indi- . The pre-test probability of bradycardia-related syncope is relatively . viduals does not necessarily preclude arrhythmia risk, particularly high when there is asymptomatic sinus bradycardia (<50 b.p.m.) or . in patients with high-risk features.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 27
Electrophysiological study
Recommendations Classa Levelb
Indications
In patients with syncope and previous myocardial infarction, or other scar-related conditions, EPS is indicated when syn- I B cope remains unexplained after non-invasive evaluation.218
In patients with syncope and bifascicular BBB, EPS should be considered when syncope remains unexplained after non-inva- IIa B sive evaluation.188,214–217,221
In patients with syncope and asymptomatic sinus bradycardia, EPS may be considered in a few instances when non-invasive IIb B tests (e.g. ECG monitoring) have failed to show a correlation between syncope and bradycardia.210–212
In patients with syncope preceded by sudden and brief palpitations, EPS may be considered when syncope remains unex- IIb C plained after non-invasive evaluation.
EPS-guided therapy
In patients with unexplained syncope and bifascicular BBB, a pacemaker is indicated in the presence of either a baseline H-V interval of >_70 ms, second- or third-degree His-Purkinje block during incremental atrial pacing, or with pharmacological I B challenge.188,214–217,221
In patients with unexplained syncope and previous myocardial infarction, or other scar-related conditions, it is recom- I B mended that induction of sustained monomorphic VT is managed according to the current ESC Guidelines for VA.46
In patients without structural heart disease with syncope preceded by sudden and brief palpitations, it is recommended that the induction of rapid SVT or VT, which reproduce hypotensive or spontaneous symptoms, is managed with appropriate I C therapy according to the current ESC Guidelines.46,222
In patients with syncope and asymptomatic sinus bradycardia, a pacemaker should be considered if a prolonged corrected IIa B SNRT is present.210–212
Additional advice and clinical perspectives • In general, whereas a positive EPS predicts the cause of syncope, a negative study is unable to exclude an arrhythmic syncope and further evalua- tion is warranted. • The induction of polymorphic VT or VF in patients with ischaemic cardiomyopathy or DCM cannot be considered a diagnostic finding of the cause of syncope. • EPS is generally not useful in patients with syncope, normal ECG, no heart disease, and no palpitations.
BBB = bundle branch block; DCM = dilated cardiomyopathy; ECG = electrocardiogram; EPS = electrophysiological study; ESC = European Society of Cardiology; SNRT = sinus node recovery time; SVT = supraventricular tachycardia; VA = ventricular arrhythmia; VF = ventricular fibrillation; VT = ventricular tachycardia. aClass of recommendation. bLevel of evidence.
. 4.2.7 Endogenous adenosine and other biomarkers . and VVS. In parallel, the adenosine/adenosine triphosphate . Established cardiac biomarkers such as troponin and B-type natriu- . (ATP) provocation test has been performed to demonstrate the retic peptide have been used to distinguish cardiac from non-cardiac . utility of adenosine sensitivity and paroxysmal cardioinhibitory 223–225 . syncope and identify structural heart disease. . propensity for the selection of appropriate pacemaker candi- . dates.4,227,228 The test requires rapid (<2 s) injection of a 20 mg . 4.2.7.1 Adenosine (triphosphate) test and plasma concentration . bolus of ATP/adenosine during ECG monitoring. The induction of The purinergic signalling system, including adenosine and its . AV block with ventricular asystole lasting >6 s, or the induction . receptors, has been proposed to be involved in unexplained . of AV block lasting >10 s, is considered abnormal. ATP testing syncope without prodrome.4,226 A low plasma adenosine level is . was positive in most patients with syncope of unknown origin . associated with paroxysmal AV block or CSS, whereas a high . (especially syncope without prodrome and without structural level is seen in those with a hypotensive/vasodepressive tendency . heart disease4) but not in controls, suggesting that paroxysmal AV
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 28 ESC Guidelines
. block could be the cause of unexplained syncope. Although car- . 4.2.7.3 Immunological biomarkers . diac pacing may lead to substantial reduction of syncopal attacks . Autoantibodies against adrenergic receptors in OH and POTS have in elderly patients with unexplained syncope and a positive ATP . been reported, but further studies are needed.232–234 229 . test, previous studies showed no correlation between . AV block induced by ATP and ECG findings (documented by ILR) . . 4.2.8 Echocardiography during spontaneous syncope.122,123,227 Thus, the low predictive . . For patients with suspected heart disease, echocardiography serves value of the test does not support its routine use in selecting . . to confirm or refute the suspicions in equal proportions and plays an patients for cardiac pacing, but rather its positivity suggests that . . important role in risk stratification.235,236 Echocardiography identifies it can be used to confirm the suspicion of asystolic syncope . . the cause of syncope in very few patients when no more tests are by means of prolonged ECG monitoring. The role of endogenous . . needed (i.e. severe aortic stenosis, obstructive cardiac tumours or adenosine release in triggering a special form of asystolic . . thrombi, pericardial tamponade, or aortic dissection).237–239 In a lit- syncope (so-called adenosine-sensitive syncope) remains under . . erature review, right and left atrial myxoma presented with syncope investigation. . . in <20% of cases.240–244 . 4.2.7.2 Cardiovascular biomarkers . . 4.2.8.1 Exercise stress echocardiography Some cardiovascular biomarkers are increased in autonomic dysfunc- . . Upright or semi-supine exercise stress echocardiography to detect tion underlying syncope, such as elevated copeptin (vasopressin), . . provocable left ventricular outflow tract obstruction should be con- endothelin-1, and N-terminal pro-B-type natriuretic peptide in . . sidered in patients with HCM that complain of exertional or postural OH,113,230,231 whereas atrial natriuretic peptide may be reduced in . . syncope, particularly when it recurs during similar circumstances (e.g. POTS.113 At present, the use of cardiovascular biomarkers in the . . when rushing upstairs or straining). A gradient of >_50 mmHg is usu- diagnosis of syncope awaits more evidence and verification in inde- . . ally considered to be the threshold at which left ventricular outflow pendent cohorts. . . tract obstruction becomes haemodynamically important.245–249
Echocardiography
Recommendations Classa Levelb
Indications
Echocardiography is indicated for diagnosis and risk stratification in patients with suspected structural heart disease.235,236 I B
Two-dimensional and Doppler echocardiography during exercise in the standing, sitting, or semi-supine position to detect provocable left ventricular outflow tract obstruction is indicated in patients with HCM, a history of syncope, and a resting I B or provoked peak instantaneous left ventricular outflow tract gradient <50 mmHg.245–249
Diagnostic criteria
Aortic stenosis, obstructive cardiac tumours or thrombi, pericardial tamponade, and aortic dissection are the most prob- I C able causes of syncope when the ECG shows the typical features of these conditions.237–244
Additional advice and clinical perspectives • For patients without suspected cardiac disease after history taking, physical examination, and electrocardiography, the ECG does not provide additional useful information, suggesting that syncope alone is not an indication for echocardiography. • Computed tomography or MRI should be considered in selected patients presenting with syncope of suspected cardiac structural origin when echocardiography is not diagnostic.
ECG = echocardiogram; HCM = hypertrophic cardiomyopathy; MRI = magnetic resonance imaging. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 29
4.2.9 Exercise stress testing Exercise-induced syncope is infrequent, and the literature is lim- Coronary angiography ited to case reports. Exercise testing should be performed in patients who have experienced episodes of syncope during or Recommendations Classa Levelb shortly after exertion. Syncope can occur during or immediately Indications after exercise. These two situations should be considered sepa- rately. Indeed, syncope occurring during exercise is likely due to In patients with syncope, the same indica- cardiac causes (even though some case reports have shown that it tions for coronary angiography should be IIa C might be a manifestation of an exaggerated reflex vasodilatation), considered as in patients without whereas syncope occurring after exercise is almost invariably due syncope.258 to a reflex mechanism.250–252 Tachycardia-related exercise- Additional advice and clinical perspectives induced second- and third-degree AV block has been shown to be Angiography alone is not diagnostic of the cause of syncope. located distal to the AV node253 and predicts progression to per- manent AV block.254,255 A resting ECG frequently shows intraven- a tricular conduction abnormalities,253,254 but cases with a normal Class of recommendation. bLevel of evidence. resting ECG have also been described.256,257 There are no data supporting an indication for exercise testing in a general popula- tion with syncope. . . 5. Treatment . . . 5.1 General principles of treatment of . Exercise testing . syncope . . The general framework of treatment is based on risk stratification Recommendations Classa Levelb . and the identification of specific mechanisms when possible (Figure 8). . . The following three general principles should be considered: Indications . . • The efficacy of therapy aimed at preventing syncope recurrence Exercise testing is indicated in patients who . . is largely determined by the mechanism of syncope rather than experience syncope during or shortly after I C . its aetiology. Bradycardia is a frequent mechanism of syncope. exertion. . . Cardiac pacing is the most powerful therapy for bradycardia but . its efficacy is less if hypotension coexists (see Table 9 and Diagnostic criteria . . Supplementary Data Table 9). The treatment of syncope due to a . hypotensive reflex or to OH is more challenging because specific Syncope due to second- or third-degree AV . block is confirmed when the AV block . therapies are less effective. I C . develops during exercise, even without . • Often, therapy to prevent recurrence differs from that for the 253–257 . underlying disease. The management of patients at high risk of syncope. . . SCD requires careful assessment of the individual patient’s risk Reflex syncope is confirmed when syncope . (see section 5.5). . is reproduced immediately after exercise in I C . • Syncopal recurrences often decrease spontaneously after medical . the presence of severe hypotension.250–252 . assessment, even in the absence of a specific therapy; in general, . syncope recurs in <50% of patients within 1–2 years (see Additional advice and clinical perspectives . . Supplementary Data Table 10). The decrease seems to be more There are no data supporting routine exercise testing in patients . evident when there is a lack of a clear anatomical substrate for with syncope. . syncope, such as in the case of reflex syncope and unexplained . . syncope. The reason for this decrease is not known. Several . potential clinical, statistical, and psychological explanations have AV = atrioventricular. . aClass of recommendation. . been provided and all probably play a role (see Supplementary b . Level of evidence. . Data Table 10). Whatever the reason, the possibility of spontane- . ous improvement has major practical importance for treatment . . that can be postponed in low-risk conditions. The consequence . of the spontaneous decrease is that any therapy for syncope pre- . vention appears to be more effective than it actually is, which 4.2.10 Coronary angiography . . makes the results of observational data on therapy questionable In patients presenting with syncope and obstructive coronary artery . . in the absence of a control group. disease, percutaneous coronary intervention is not associated with a . significant reduction in readmission for syncope.258 Angiography . . alone is not diagnostic of the cause of syncope. Therefore, cardiac . catheterization techniques should be carried out in suspected myo- . 5.2 Treatment of reflex syncope . cardial ischaemia or infarction with the same indications as for . Despite its benign course, recurrent and unpredictable reflex syn- patients without syncope. . cope may be disabling. The cornerstone of management of these
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 30 ESC Guidelines
Figure 8 General framework of treatment is based on risk stratification and the identification of specific mechanisms when possible. ARVC = arrhythmogenic right ventricular cardiomyopathy; CAD = coronary artery disease; DCM = dilated cardiomyopathy; ECG = electrocardiographic; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter defibrillator; LQTS = long QT syndrome; SCD = sudden cardiac death.
Table 9 Expected syncope recurrence rates with a permanent pacemaker in different clinical settings (for more details see Supplementary Data Table 9).
Clinical setting Expected 2-year syncope recurrence rate with cardiac pacing
Syncope due to established bradycardia and absence of hypotensive mechanism High efficacy (<_5% recurrence rate)
Syncope due to established bradycardia and associated hypotensive mechanism Moderate efficacy (5–25% recurrence rate)
Syncope due to suspected bradycardia and associated hypotensive mechanism Low efficacy (>25% recurrence rate)
patients is non-pharmacological treatment, including education, . 5.2.1 Education and lifestyle modifications . lifestyle modification, and reassurance regarding the benign nature of . Education and lifestyle modifications have not been evaluated in the condition. . randomized studies, but there is a consensus for implementing them . Additional treatment may be necessary in patients with severe forms, . as first-line therapy in all cases. These comprise reassurance about as defined in Web Practical Instructions section 2.3, in particular: when . the benign nature of the disease, education regarding awareness and the . very frequent syncope alters quality of life; when recurrent syncope . possible avoidance of triggers and situations (e.g. dehydration and/or without, or with a very short, prodrome exposes the patient to a risk of . hot crowded environments), and the early recognition of prodromal . trauma; and when syncope occurs during a high-risk activity (e.g. driving, . symptoms in order to sit or lie down and activate counter-pressure machine operation, flying, or competitive athletics, etc.). Only 14% of . manoeuvres without delay. If possible, triggers should be addressed . the highly selected population with reflex syncope who are referred to . directly, such as cough suppression in cough syncope, micturition in the 186 . specialized syncope units may need such additional treatment. In gen- . sitting position, etc. Increased intake of oral fluids is also advised. Salt . eral, no therapy is appropriate for every form of reflex syncope. The . supplementation at a dose of 120 mmol/day of sodium chloride has most important discriminant for the choice of therapy is age. A decision . been proposed.259 In general, >50% of patients with recurrent syncopal . pathway for the selection of a specific therapy according to age, severity . episodes in the 1 or 2 years before evaluation do not have syncopal of syncope, and clinical forms is summarized in Figure 9. . recurrences in the following 1 or 2 years and, in those with recurrences,
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 31
Figure 9 Schematic practical decision pathway for the first-line management of reflex syncope (based on patient’s history and tests) according to age, severity of syncope, and clinical forms. Younger patients are those aged <40 years while older patients are >60 years, with an overlap between 40 and 60 years. Severity of reflex syncope is defined in the text. The duration of prodrome is largely subjective and imprecise. A value of <_5 s distinguishes arrhythmic from reflex syncope49; in patients without structural heart disease, a duration >10 s can distinguish reflex syncope from cardiac syncope.38 In practice, the prodrome is ‘absent or very short’ if it does not allow patients enough time to act, such as to sit or lie down. The heading’ low BP phe- notype’ identifies patients with chronic low BP values (in general, systolic around 110 mmHg, who have a clear history of orthostatic intolerance and orthostatic VVS). The group ‘dominant cardioinhibition‘ identifies patients in whom clinical features and results of tests suggest that sudden cardioinhibi- tion is mainly responsible for syncope. One such clue is lack of prodrome, so patients without prodromes may, after analysis, fall into this category. Remark: Overlap between subgroups is expected. In selected cases, pacing may be used in patients aged <40 years. This Task Force cannot give recommendations due to the lack of sufficient evidence from studies. In selected cases, fludrocortisone may be used in patients aged >60 years. This Task Force cannot give recommendations due to the lack of sufficient evidence from studies. Midodrine can be used at any age even if existing studies were performed in young patients. Patients with short or no prodrome should continue investigations to identify the underlying mechanism and guide subsequent therapy. Sometimes an ILR strategy should also be considered in patients aged <40 years. BP = blood pressure; ILR = implantable loop recorder; VVS = vasovagal syncope. aSpontaneous or provoked by, sequentially, carotid sinus massage, tilt testing, or ILR.
. the burden of syncope decreases by >70% compared with the . Despite the lack of controlled studies, there is strong consensus . preceding period. The effect of education and reassurance is . that education and lifestyle modifications have a high impact probably the most likely reason for the decrease in syncope . in reducing recurrence of syncope. . (see Supplementary Data Table 10). An example of a patient instruction . sheet can be found in the Web Practical Instructions section 9.1: European . 5.2.2 Discontinuation/reduction of hypotensive therapy . Society of Cardiology information sheet for patients affected by reflex . Careful avoidance of agents that lower BP, i.e. any antihyperten- syncope. . sive agents, nitrates, diuretics, neuroleptic antidepressants, or
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 32 ESC Guidelines
. dopaminergic drugs, is key in the prevention of recurrence of syn- . There is sufficient evidence from multiple trials that tilt train- cope. In a small randomized trial260 performedin58patients . ing has little efficacy in reducing recurrence of syncope in . (mean age 74 ± 11 years) affected by vasodepressor reflex syn- . young patients with long-lasting recognizable prodromal symp- cope diagnosed by tilt testing or CSM, who were taking on average . toms. Further research is unlikely to have an important impact . 2.5 hypotensive drugs, discontinuation or reduction of the vasoac- . on our confidence in the estimate. tive therapy caused a reduction of the rate of the primary com- . . bined endpoint of syncope, presyncope, and adverse events from . 50 to 19% (hazard ratio 0.37) compared with a control group who . 5.2.5 Pharmacological therapy . continued hypotensive therapy during a follow-up of 9 months. In . Pharmacological therapy may be considered in patients who have the Systolic Blood Pressure Intervention Trial,261 patients at high . recurrent syncope despite education and lifestyle modifications . cardiovascular risk who were already using antihypertensive drugs . including training in PCM. Many drugs have been tested in the treat- targeting a systolic BP of 120 mmHg had an approximately two- . ment of reflex syncope, for the most part with disappointing results. . fold risk of syncope vs. the control group targeting a systolic BP of . While results have been satisfactory in uncontrolled trials or short- 262 . 140 mmHg. In a short-term randomized trial conducted in 32 . term controlled trials, several long-term placebo-controlled prospec- patients affected by CSS, withdrawal of vasodilator therapy . tive trials have not shown a benefit of the active drug over placebo, . reduced the magnitude of the vasodepressor reflex induced by . with some exceptions. CSM. . . . 5.2.5.1 Fludrocortisone . There is moderate evidence that discontinuation/reduction of . Fludrocortisone, by increasing renal sodium reabsorption and hypotensive therapy targeting a systolic BP of 140 mmHg . . expanding plasma volume, may counteract the physiological cascade should be effective in reducing syncopal recurrences in patients . leading to the orthostatic vasovagal reflex.273 The mechanism of with hypotensive susceptibility. Further research is likely to . . action can be compared with that of saline infusion, which has also have an important impact on our confidence in the estimate. . proved effective in acute tilt test studies.274 The Prevention of . 275 . Syncope Trial (POST) 2 enrolled 210 young (median age 30 years) . patients with low–normal values of arterial BP and without comor- 5.2.3 Physical counter-pressure manoeuvres . . bidities, and randomized them to receive fludrocortisone (titrated at Isometric muscle contractions increase cardiac output and arterial BP . . a dosage of 0.05–0.2 mg once per day) or placebo. The primary end- during the phase of impending reflex syncope. Three clinical stud- . . point showed only a marginal non-significant reduction in syncope in ies119,120,263 and one prospective multicentre randomized trial121 . . the fludrocortisone group compared with the placebo group (hazard assessed the effectiveness of physical counter-pressure manoeuvres . . ratio 0.69, 95% CI 0.46–1.03; P=0.069), which became more signifi- (PCM) of the legs or arms and showed that they allowed the patient . . cant when the analysis was restricted to patients who achieved 0.2 to avoid or delay losing consciousness in most cases. In the Physical . 121 . mg/day dose stabilization at 2 weeks. The clinical benefit of fludrocor- Counterpressure Manoeuvres Trial (PC-Trial), 223 patients aged . . tisone therapy was modest: at 12 months, 44% of patients in the flu- 38 ± 15 years with recurrent reflex syncope and recognizable pro- . . drocortisone arm continued to suffer syncope, a rate only slightly dromal symptoms were randomized to receive standardized conven- . . lower than the 60.5% rate observed in the placebo arm. In the mean- tional therapy alone or conventional therapy plus training in PCM. . . time, a similar number of patients discontinued fludrocortisone ther- Actuarial recurrence-free survival was better in the PCM group . . apy owing to side effects, thus equating the benefit/risk ratio. (log-rank P=0.018), resulting in a relative risk reduction of 39% (95% . . Fludrocortisone should not be used in patients with hypertension or CI 11–53). No adverse events were reported. A limitation of this . . heart failure. Fludrocortisone was ineffective in a small randomized treatment is that it cannot be used in patients with short or absent . 276 . double-blind trial in children. prodrome and that PCM are less effective in patients older than 60 . years.264 An instruction sheet on how to perform PCM can be found . . There is moderate evidence that fludrocortisone may be effec- in the Web Practical Instructions section 9.2. . . tive in reducing syncopal recurrences in young patients with . lownormal values of arterial BP and without comorbidities. There is moderate evidence that PCM is effective in reducing . . Further research is likely to have an important impact on our syncopal recurrences in patients <60 years old with long- . . confidence in the estimate of effect. lasting recognizable prodromal symptoms. . . . . 5.2.5.2 Alpha-agonists 5.2.4 Tilt training . As failure to achieve proper vasoconstriction of the peripheral ves- . In highly motivated young patients with recurrent vasovagal symp- . sels is common in reflex syncope, alpha-agonist vasoconstrictors (eti- toms triggered by orthostatic stress, the prescription of progressively . lefrine and midodrine) have been used. Etilefrine has been studied in . 277 prolonged periods of enforced upright posture (so-called tilt training) . a large randomized placebo-controlled double-blind trial. During 265 . has been proposed to reduce syncope recurrence. While some . follow-up, patients treated twice daily with etilefrine 25 mg or pla- 266,267 . studies suggested modest benefit with outpatient tilt training, . cebo showed no difference in the frequency of syncope or the time most controlled trials reported no significant effect.268–272 . to recurrence. Midodrine [usually 2.5–10 mg, three times daily (t.i.d)] . Moreover, this treatment is hampered by the low compliance of . has proved effective in small studies but none satisfied the criteria of patients in continuing the training programme for a long period. . a pivotal clinical trial. A recent systematic review of these trials278
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 33
. 287 showed that the confidence in estimates was moderate because of . orthostatic VVS. Norepinephrine transport inhibitors (reboxetine . imprecision and publication bias. The most frequent side effects that . and sibutramine) lead to a selective increase in sympathetic tone dur- led to discontinuation of midodrine were supine hypertension, pilo- . ing stress by inhibiting the reuptake of norepinephrine in sympathetic . motor reactions, and urinary problems (urinary retention, hesitancy, . neuronal synapses. In double-blind, randomized, crossover fashion, or urgency). The major limitation of midodrine is frequent dosing, . reboxetine and sibutramine block or attenuate the vasovagal reflex . 288 which limits long-term compliance. Overall, these data suggest that . during tilt testing. In an open-label prospective clinical study in chronic pharmacological treatment with alpha-agonists alone may be . seven very symptomatic patients who had not responded to any pre- . of little use in reflex syncope and that long-term treatment cannot be . vious treatment, sibutramine achieved 94% suppression of syncopal advised for occasional symptoms. . episodes at 6 months.289 . . Ganglionic plexus ablation. Radiofrequency ablation of vagal ganglia There are contrasting results from multiple trials that alpha- . located close to the sinus node and AV node was reported to abolish . agonists may be effective in reducing syncopal recurrences in . the vagal efferent output during VVS in some observational studies . 290,291 patients with the orthostatic form of VVS. Further research is . and case reports. However, owing to a weak rationale, small likely to have an important impact on our confidence in the . populations, weak documentation of follow-up results, procedural . estimate. . risks, and lack of control groups, the current evidence is insufficient . to confirm the efficacy of vagal ganglia ablation. . 5.2.5.3 Beta-blockers . Beta-blockers have been presumed to lessen the degree of ventricu- . . lar mechanoreceptor activation owing to their negative inotropic . 5.2.6 Cardiac pacing effect in reflex syncope. This theory has not been supported by the . . Permanent pacemaker therapy may be effective if asystole is a domi- outcome of clinical trials. Beta-blockers failed to be effective in VVS . nant feature of reflex syncope. Establishing a relationship between 279,280 . in two randomized double-blind controlled trials. Arationale . symptoms and bradycardia should be the goal of the clinical evalua- . for the use of beta-blockers in other forms of neutrally-mediated syn- . tion of patients with syncope and a normal baseline ECG. The efficacy cope is lacking. It should be emphasized that beta-blockers may . of pacing depends on the clinical setting. A comparative table of . enhance bradycardia in CSS. . results in different settings is reported in the Supplementary Data . Table 9. Figure 10 summarizes the recommended indication for . There is sufficient evidence from multiple trials that beta- . pacing. blockers are not appropriate in reducing syncopal recurrences. . . Desirable and undesirable effects are closely balanced. . 5.2.6.1 Evidence from trials in suspected or certain reflex syncope and . electrocardiogram-documented asystole . 5.2.5.4 Other drugs . In two observational studies, cardiac pacing reduced syncope burden . 184 200 Paroxetine, a selective serotonin reuptake inhibitor, was effective in . in patients with documented asystolic syncope by 92 and 83%, one placebo-controlled trial, which included highly symptomatic . but did not prevent all syncopal events. In the randomized 281 . patients from one institution. This finding has not been confirmed . double-blind Third International Study on Syncope of Uncertain in other studies and has no experimental support. Conversely, . Etiology (ISSUE)-3 trial,185 77 patients who had documentation, by . human studies with different subtypes of serotonin-receptor antago- . means of ILR, of syncope with >_3-s asystole or >_6-s asystole without 1,282 . nists demonstrated a decreased tolerance to tilt. In a small . syncope were randomly assigned to receive either dual-chamber pac- 283 . randomized trial, benzodiazepine was as effective as metoprolol. . ing with rate drop response or sensing only. During follow-up, the 2- 284 . A somatostatin analogue (octreotide) was used in a few patients . year estimated rate of syncope recurrence was 57% with pacemaker affected by orthostatic intolerance and its effect cannot be properly . off and 25% with pacemaker on (log-rank P 0.039). The risk of . ¼ evaluated. . recurrence was reduced by 57%. In the ILR subgroup of the multi- . 292 . centre Syncope Unit Project (SUP) 2 study, the estimated rates of 5.2.5.5 Emerging new therapies in specific subgroups . syncope recurrence with pacing were 11% at 1 year, 24% at 2 years, Low-adenosine phenotype. In a series of case reports, theophylline . . and 24% at 3 years, and were significantly lower than the correspond- appeared effective in patients with recurrent sudden onset (pre)syn- . ing rates observed in untreated control patients. The above evidence . cope who presented with the common biological characteristic of . supports a class IIa recommendation low circulating adenosine levels.285,286 Theophylline is a non-selective . . adenosine receptor antagonist that is potentially effective when . There is sufficient evidence that dual-chamber cardiac pacing adenosine is suspected to be involved in the mechanism of syncope. . should be considered to reduce recurrence of syncope when . An intra-patient comparison between a period with and a period . the correlation between symptoms and ECG is established in without theophylline therapy, with the support of prolonged ECG . patients 40 years of age with the clinical features of those in . monitoring, showed that symptoms disappeared and the number of . the ISSUE studies. prolonged asystolic pauses was impressively reduced from a median . . of 1.11 per month during 13 months of no treatment to 0 per month . 5.2.6.2 Evidence from trials in patients with carotid sinus syndrome during 20 months of theophylline treatment. . The evidence supporting the benefit of cardiac pacing in patients . Low-norepinephrine phenotype. A mismatch between sympathetic . affected by cardioinhibitory CSS is limited to a few small controlled nerve activity and norepinephrine spillover is present in patients with . trials and retrospective observational studies. In a review293 including
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 34 ESC Guidelines
Figure 10 Summary of indications for pacing in patients with reflex syncope. CI-CSS = cardioinhibitory carotid sinus syndrome.
12 studies for a total of 601 paced and 305 unpaced patients, the syn- . 5.2.6.3 Evidence from trials in patients with tilt-induced vasovagal . copal recurrence rate during follow-up ranged from 0–20% with pac- . syncope . ing, whereas the recurrence of syncope was always higher in . Effectiveness of pacing in patients with tilt-induced VVS has been untreated patients, who showed a rate between 20–60%. In a meta- . studied in five multicentre RCTs.296–300 When combining the results 293 . analysis of the three studies with a control group of untreated . of these trials, 318 patients were evaluated; syncope recurred in 21% patients, syncope recurred in 9% of 85 paced patients and in 38% of . of the paced patients and in 44% of unpaced patients (P < 0.001). A . 91 controls (relative risk 0.24, 95% CI 0.12–0.48). In a single-centre . meta-analysis of all studies suggested a non-significant 17% reduction registry of 169 consecutive patients treated with pacemakers, the . in syncope from the double-blind studies, and an 84% reduction in . 301 actuarial estimate of syncopal recurrence was 7% at 1 year, 16% at . the studies where the control group did not receive a pacemaker. 3 years, and 20% at 5 years.90 In the CSS subgroup of the multicentre . In general, pacing was ineffective in trials that enrolled patients with- 292 . 299,300 SUP 2 study, the estimated syncope recurrence rates with pacing . out an asystolic tilt response. All of these studies have limita- were 9% at 1 year, 18% at 2 years, and 20% at 3 years, and were signif- . tions, and a direct comparison is somewhat difficult because of . icantly lower than the corresponding rates observed in untreated . important differences in study design, largely focused on patient controls, which were 21%, 33%, and 43%, respectively. Given the . selection. Overall, in typical vasovagal populations, pacing seems to . similar outcome of patients with reflex spontaneous asystolic pauses . have marginal efficacy. and those with CSS, this Task Force voted to downgrade the recom- . The rationale for the efficacy of cardiac pacing is that the cardioin- . mendation for pacing in patients with CSS from class I (as in the 2013 . hibitory reflex is dominant in some patients, as there is no role for 294 . ESC Pacing Guidelines ) to class IIa. . pacing in the preventing vasodilatation and hypotension. In a substudy . 302 . of the ISSUE-3 trial, an asystolic response during tilt testing pre- Despite the lack of large RCTs, there is sufficient evidence that . dicted a similar asystolic form during spontaneous ILR-documented . dual-chamber cardiac pacing should be considered to reduce . syncope, with a positive predictive value of 86%. In the tilt subgroup syncopal recurrences in patients affected by dominant cardi- . of the SUP 2 study,292 among 38 patients with dominant cardioinhibi- . oinhibitory CSS. . tory reflex (with a mean asystolic pause of 22 ± 16 s) the estimated . rates of syncope recurrence with pacing were 3% at 1 year, 17% at 2 . Two variables are well known to hamper the efficacy of pacing ther- . years, and 23% at 3 years; these figures were significantly lower than 93,98 . apy in CSS: the mixed forms (see also Web Practical Instructions . the corresponding rates observed in untreated controls, and were section 5) and the association with positivity of tilt testing. Patients . similar to those observed in patients with CSS or with ECG- . who have positive tilt tests have a three-fold greater probability of . documented asystole. In a recent multicentre crossover RCT per- syncope recurrence after dual chamber pacing than those with nega- . formed in 46 patients aged >40 years, affected by severely recurrent 293,295 . 303 tive tilt tests ; thus, when tilt testing is positive, caution must be . (>5 episodes during life) cardioinhibitory VVS, during 24-month recommended over pacemaker implantation. . follow-up, syncope recurred in 4 (9%) patients treated with a dual-
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 35
. chamber pacemaker with closed-loop stimulation compared with 21 . dual-chamber cardiac pacing significantly reduced the 2-year syncope . (46%) patients who had received a sham pacemaker programmed off . recurrence rate from 69% in the control group to 23% in the active (P=0.0001). . group. 205 . Adding video recording to tilt testing, Saal et al. recently . showed, in patients with asystole, that asystole occurred 3 s . There is weak evidence that dual-chamber cardiac pacing . before syncope or later in one-third of patients, in whom cardioinhi- . may be useful in reducing recurrences of syncope in patients bition was too late to have primarily caused syncope; in the other . with the clinical features of adenosine-sensitive syncope. . two-thirds of asystolic tilt responses, the cause must have been . The documentation of possible bradyarrhythmia in sponta- mainly cardioinhibition or a combination of cardioinhibition and . neous syncope remains the preferred eligibility criterion for . vasodepression. . pacing. The clinical presentation is probably as important as tilt test . . positivity when selecting patients who can benefit from cardiac . 5.2.6.5 Choice of pacing mode . 304,305 306 pacing. The SUP 2 study population was characterized by higher . In CSS, a few small controlled studies and one registry mean age, history of recurrent syncope beginning in middle or . showed that dual-chamber pacing is better than the single chamber . older age, and frequent injuries, probably due to presentation . ventricular mode in counteracting BP fall during CSM and in prevent- 292 . without warning. . ing symptom recurrences. Even if the quality of evidence is weak, . . dual-chamber pacing is widely preferred in clinical practice. Owing to the contrasting results of the randomized trials, the . In patients with VVS, dual-chamber pacing was used mostly with . estimated benefit of dual-chamber pacing in cardioinhibitory . a rate drop response feature that instituted rapid dual-chamber tilt-positive patients is weak. Divergence of opinion exists . pacing if the device detected a rapid decrease in HR. A compari- . among experts. Further research is very likely to have an . son between dual-chamber closed-loop stimulation and conven- important impact on recommendations. Conversely, there is . tional dual-chamber pacing has been performed by means of a . strong consensus that pacing cannot be offered to patients . crossover design in two small studies; these studies showed fewer with non-cardioinhibitory tilt-positive response, and further . syncope recurrences with closed-loop stimulation, both in the . 307 tests (e.g. ILR) are warranted to document the mechanism of . acute setting during repeated tilt testing and during 18-month the spontaneous reflex. . clinical follow-up.308 . . 5.2.6.4 Evidence from trials in patients with adenosine-sensitive syncope . 5.2.6.6 Selection of patients for pacing and proposed algorithm . Under this term, classified as a non-classical form of reflex syn- . The fact that pacing is effective does not mean that it is always neces- cope in Table 3, different clinical conditions are included, which . sary. In patients with reflex syncope, cardiac pacing should be the last . have a supposed role of adenosine in the genesis of syncope in . choice and should only be considered in highly selected patients, i.e. common. . those >_40 years of age (mostly >60 years), affected by severe forms . A new clinical entity, called idiopathic AV block, has recently . of reflex syncope with frequent recurrences associated with a been described in patients with a long history of syncope and in . high risk of injury, often due to the lack of prodrome.186 While there . whom paroxysmal AV block could be recorded at the time of syn- . is growing scepticism over the diagnostic accuracy of tilt testing for 5 . cope recurrence. These patients had an otherwise normal heart . syncope diagnosis, emerging evidence supports the use of tilt testing and no sign of conduction disease on ECG and EPS; they had very . for the assessment of reflex hypotensive susceptibility132, which may be . low plasma adenosine levels and a high induction rate of transient . considered to identify patients with an associated hypotensive . complete heart block during exogenous injections of adenosine. . response who would be less likely to respond to permanent cardiac No syncope recurrence was observed after permanent cardiac . pacing (see section 4.2.2.2). In a meta-analysis309 of individual patient . pacing over very long periods of follow-up and there was no per- . data from four studies performed in patients with asystolic reflex manent AV block. . syncope documented by an ILR, the estimated 3-year recurrence . Similarly, the entity of ‘low-adenosine syncope’hasrecently . rate of syncope was 2% (95% CI ± 4%) in tilt-negative patients and been described in patients who have an otherwise unexplained . 33% (95% CI ± 20%) in tilt-positive patients; a positive tilt test . syncope with sudden onset without prodrome, a normal heart, . response was the only significant predictor of syncope recurrence and normal ECG.4 The clinical, laboratory, and biological features . with a hazard ratio of 4.3. Patients with hypotensive susceptibility . of these patients are similar to those observed in patients . should need measures directed to counteract hypotensive suscepti- affected by idiopathic paroxysmal AV block. Unlike in VVS, tilt . bility in addition to cardiac pacing, e.g. the discontinuation/reduction 4,226 . testing is usually negative. No syncope recurrence was . of hypotensive drugs and the administration of fludrocortisone or observed after permanent cardiac pacing in 10 patients who had . midodrine. . ECG documentation of asystolic pause due to sinus arrest or AV . The algorithm shown in Figure 11 has recently been prospectively 286 . block. . validated in a multicentre pragmatic study, which showed a low In a small multicentre trial227 performed in 80 highly selected eld- . recurrence rate of syncope with pacing of 9% at 1 year and 15% at 2 . erly patients with unexplained unpredictable syncope who had a pos- . years, significantly lower than the 22% and 37%, respectively, itiveresponsetointravenousinjectionofabolusof20mgofATP, . observed in unpaced controls.186
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 36 ESC Guidelines
Treatment of reflex syncope
Recommendations Classa Levelb
Education and lifestyle modifications
Explanation of the diagnosis, the provision of reassurance, and explanation of the risk of recurrence and the avoidance of I B triggers and situations are indicated in all patients. Supplementary Data Table 10
Discontinuation/reduction of hypotensive therapy
Modification or discontinuation of hypotensive drug regimen should be considered in patients with vasodepressor syncope, IIa B if possible.260–262
Physical manoeuvres
Isometric PCM should be considered in patients with prodromes who are <60 years of age.119–121,263,264 IIa B
Tilt training may be considered for the education of young patients.265–272 IIb B
Pharmacological therapy
Fludrocortisone may be considered in young patients with the orthostatic form of VVS, low–normal values of arterial BP, IIb B and the absence of contraindication to the drug.275
Midodrine may be considered in patients with the orthostatic form of VVS.278 IIb B
Beta-adrenergic blocking drugs are not indicated.279,280 III A
Cardiac pacing
Cardiac pacing should be considered to reduce syncopal recurrences in patients aged >40 years, with spontaneous docu- mented symptomatic asystolic pause(s) >3 s or asymptomatic pause(s) >6 s due to sinus arrest, AV block, or the combina- IIa B tion of the two.184,185,200,292
Cardiac pacing should be considered to reduce syncope recurrence in patients with cardioinhibitory carotid sinus syn- IIa B drome who are >40 years with recurrent frequent unpredictable syncope.90,292,293
Cardiac pacing may be considered to reduce syncope recurrences in patients with tilt-induced asystolic response who are IIb B >40 years with recurrent frequent unpredictable syncope.292,297,298,303
Cardiac pacing may be considered to reduce syncope recurrences in patients with the clinical features of adenosine-sensi- IIb B tive syncope.5,227,286
Cardiac pacing is not indicated in the absence of a documented cardioinhibitory reflex.299,300 III B
Additional advice and clinical perspectives • In general, no therapy can completely prevent syncope recurrence during long-term follow-up. A decrease of the syncope burden is a reasonable goal of therapy. • The fact that pacing may be effective does not mean that it is also always necessary. It must be emphasized that the decision to implant a pace- maker needs to be made in the clinical context of a benign condition that frequently affects young patients. Thus, cardiac pacing should be limited to a highly selected small proportion of patients affected by severe reflex syncope. Patients suitable for cardiac pacing are older with a history of recurrent syncope beginning in middle or older age and with frequent injuries, probably due to presentation without warning. Syncope recur- rence is still expected to occur despite cardiac pacing in a minority of patients. • Tilt test response is the strongest predictor of pacemaker efficacy.309 Patients with a negative tilt test response will have a risk of syncope recur- rence of as low as that observed in patients paced for intrinsic AV block. Further research is very unlikely to change the confidence in the esti- mate of effect. On the contrary, patients with a positive tilt test response will have a higher risk of recurrence of syncope with a large confidence range, which makes any estimate of the benefit of pacing uncertain. Further research is warranted.
AV = atrioventricular; BP = blood pressure; PCM = physical counter-pressure manoeuvres; VVS = vasovagal syncope. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 37
No
No
Asystolic tilt testing?
No
No
Figure 11 Decision pathway for cardiac pacing in patients with reflex syncope. CI-CSS = cardioinhibitory carotid sinus syndrome; CSM = carotid sinus massage; DDD PM = dual-chamber pacemaker; ILR = implantable loop recorder.
. 310 5.3 Treatment of orthostatic hypotension . chloride. Rapid ingestion of cool water is reported to be effective in . combating orthostatic intolerance and postprandial hypotension.311 and orthostatic intolerance syndromes . Current management strategies for OH are summarized in Figure 12. . . . . 5.3.3 Discontinuation/reduction of vasoactive drugs 5.3.1 Education and lifestyle measures . Several studies that have evaluated the association of vasoactive Education regarding the nature of the condition in conjunction with the . . drugs (i.e. any antihypertensive agents, nitrates, diuretics, neuroleptic lifestyle advice outlined in section 5.2.1 can markedly improve ortho- . antidepressants, or dopaminergic drugs) with OH and falls static symptoms, even though the rise in BP is relatively small (10–15 . 312 . have yielded contrasting results. However, intensely prescribed mmHg); raising standing BP to just within the autoregulatory zone can . antihypertensive therapy can increase the risk of OH. Intensive anti- make a substantial functional difference. Ambulatory BP recordings may . . hypertensive treatment can be defined as higher doses of antihyper- be helpful in identifying abnormal diurnal patterns. These recordings may . tensive medications, an increased number of antihypertensive also help identify supine or nocturnal hypertension in treated patients. . . drugs, or lowering BP to a target <140/90 mmHg. The total . 313 . number of BP-lowering medications or the use of three or more . 314 5.3.2 Adequate hydration and salt intake . antihypertensive drugs may be a significant predictor of OH. The expansion of extracellular volume is an important goal. In the . Angiotensin-converting enzyme inhibitors, angiotensin receptors . absence of hypertension, patients should be instructed to have a sufficient . blockers, and calcium channel blockers are less likely to be associated salt and water intake, targeting 2–3 L of fluids per day and 10 g of sodium . with OH compared with beta-blockers and thiazide diuretics.315–318
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 38 ESC Guidelines
Figure 12 Schematic practical guide for the treatment of orthostatic hypotension.
The principal treatment strategy in drug-induced autonomic . 5.3.8 Fludrocortisone . failure is eliminating the offending agent. The quality of evi- . Fludrocortisone (0.1–0.3 mg once daily) is a mineralocorticoid that . 327 dence is moderate. Longer-term future RCTs are likely to have . stimulates renal sodium retention and expands fluid volume. The an important impact on determining the net risk2benefit ratio . evidence in favour of fludrocortisone is from two small observational . of the withdrawal of culprit medications. . studies (in combination with head-up sleeping) and one double-blind . trial in 60 patients; the observational studies showed haemodynamic . 5.3.4 Counter-pressure manoeuvres . benefit and, in the trial, treated patients were less symptomatic with . higher BP.322,327,328 PCM such as leg crossing and squatting should be encouraged in . patients with warning symptoms who are able to perform them.319 . . The desirable effects of fludrocortisone outweigh the undesirable . effects. The quality of evidence is moderate and further research 5.3.5 Abdominal binders and/or support stockings . . is likely to have an important impact on the estimate of benefit. Gravitational venous pooling in older patients can be treated with . 23,320,321 . abdominal binders or compression stockings. . . . 5.3.9 Additional therapies . Additional and less frequently used treatments, alone or in combina- 5.3.6 Head-up tilt sleeping . . tion, include desmopressin in patients with nocturnal polyuria, Sleeping with the head of the bed elevated (>10 degrees) prevents . . octreotide in postprandial hypotension, erythropoietin in anaemia, nocturnal polyuria, maintains a more favourable distribution of body . 104,322,323 . pyridostigmine, the use of walking sticks, frequent small meals, and fluids, and ameliorates nocturnal hypertension. . . the judicious exercise of leg and abdominal muscles, especially swim- . 104 . ming. Their efficacy is less established. 5.3.7 Midodrine . The alpha-agonist midodrine is a useful addition to first-line treatment . . in patients with chronic autonomic failure. It cannot be regarded as a . 5.3.10 Emerging new pharmacological therapy in specific cure, nor is it helpful in all affected patients, but it is very useful in . subgroups . some. There is no doubt that midodrine increases BP both in the . Droxidopa, a precursor of norepinephrine, is a centrally and periph- supine and upright posture, and ameliorates the symptoms of OH. . erally acting alpha/beta-agonist approved by the US Food and Drug . Midodrine (2.5–10 mg t.i.d) was shown to be effective in three . Administration for the treatment of symptomatic neurogenic OH. 324–326 . randomized placebo-controlled trials. . Droxidopa has recently been investigated for the treatment of neu- . 329–332 . rogenic OH in four short-term RCTs with a total of 485 The desirable effects of midodrine outweigh the undesirable . patients. They showed a modest increase in standing systolic BP and . effects. The quality of evidence is moderate and further research . the symptom benefit of droxidopa over placebo regarding some is likely to have an important impact on the estimate of benefit. . items of quality of life after 2 weeks of treatment, but its benefit was
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 39
. . 5.4.1.1 Sinus node disease Treatment of orthostatic hypertension . In general, cardiac pacemaker therapy is indicated and has proved . . effective in intrinsic sinus node disease when intermittent sinus arrest a b . Recommendations Class Level . or sinoatrial block has been demonstrated to account for syncope by . means of ECG documentation during spontaneous syncope.334–338 Explanation of the diagnosis, the provision . . A frequent situation is that of patients who have prolonged sinus of reassurance, and explanation of the risk . I C . pause following the termination of tachycardia in bradycar- of recurrence and the avoidance of triggers . . dia-tachycardia syndrome due to the abnormally prolonged time and situations are indicated in all patients. . . needed for the recovery of automaticity by a diseased sinus node. . Adequate hydration and salt intake are . Permanent pacing does not affect survival. 310,311 I C . indicated. . . When the correlation between symptoms and ECG is estab- Modification or discontinuation of hypoten- . . lished, there is general consensus that cardiac pacing is effec- sive drug regimens should be IIa B . . tive and useful for symptom relief. considered.312–318 . . In the absence of the above situations, despite adequate pacing, syn- . 339–341 319 . cope recurs in approximately 15–28% of patients at 5 years Isometric PCM should be considered. IIa C . . (see Supplementary Data Table 9). This is due to the frequent associa- . Abdominal binders and/or support stockings . tion of a vasodepressor reflex mechanism with sinus node disease. In IIa B . to reduce venous pooling should be . patients with sinus node disease and syncope, carotid sinus hypersen- considered.23,320,321 . . sitivity and a positive response to tilt are present in <_50% of patients. Head-up tilt sleeping (>10 degrees) to . Thus, an increased susceptibility to neurally mediated bradycardia/ . 135,136 increase fluid volume should be IIa C . hypotension is often the cause of syncope. A reflex mechanism 104,322,323 . considered. . of syncope fits well with the unpredictable natural history of syncope . recurrence. Physicians should be aware that effectiveness of therapy is Midodrine should be considered if symp- . IIa B . not well documented in such cases. From a practical perspective, car- 324–326 . toms persist. . diac pacing may be a reasonable solution in patients affected by sinus . Fludrocortisone should be considered if . node disease, who have had documentation of an asymptomatic ven- IIa C . 322,327,328 . tricular pause >3 s (with exceptions for young trained persons, during symptoms persist. . . sleep, and medicated patients), when a competitive diagnosis, i.e. Additional advice and clinical perspectives . 294 . hypotension, can be ruled out. An abnormal SNRT enhances the • In individuals with established OH and risk factors for falls, . probability of efficacy of cardiac pacing (see section 4.2.6.1).210–212 aggressive BP-lowering treatment should be avoided; their . . treatment targets should be revised to a systolic BP value of . When the correlation between symptoms and ECG is not 140–150 mmHg and medication withdrawal should be . . established, cardiac pacing may be reasonable in patients with considered. . intrinsic sinus node disease, syncope, and documentation of . • The BP-lowering agents (angiotensin-converting enzyme . asymptomatic pause(s). inhibitors, angiotensin receptor blockers, and calcium channel . The elimination of drugs that may exacerbate or unmask an underly- . blockers) should be used preferentially, especially among . ing susceptibility to bradycardia is an important element in preventing patients at high risk of falls, as diuretics and beta-blockers are . syncope recurrence. Percutaneous cardiac ablative techniques for . associated with OH and falls and should be avoided in at-risk . the control of atrial tachyarrhythmia have become of increasing . individuals. . importance in selected patients with the bradycardia-tachycardia . . form of sick sinus syndrome, but are infrequently used for the pre- BP = blood pressure; OH = orthostatic hypertension; PCM = physical counter- . vention of syncope. pressure manoeuvres. . aClass of recommendation. . bLevel of evidence. . 5.4.1.2 Atrioventricular conduction system disease . . Cardiac pacing is the treatment of syncope associated with sympto- . matic AV block (Figure 13). Although formal RCTs of pacing in third- lost after 8 weeks.333 Thus, current evidence is insufficient to confirm . . or second-degree type 2 AV block have not been performed, some the efficacy of droxidopa for long-term use. . . observational studies suggest that pacing is highly effective in prevent- . . ing syncope recurrences when AV block is documented. Langenfeld 5.4 Cardiac arrhythmias as the primary . 341 . et al. observed a decline in the rate of syncope from 44 to 3.4% cause . over 5-year follow-up in 115 patients paced for AV block; the recur- . 5.4.1 Syncope due to intrinsic sinoatrial or . rence rate was 7% in the subgroup with syncope before pacemaker . 200 atrioventricular conduction system disease . implantation. More recently, Sud et al. reported no syncope recur- . 255 Current management strategies in patients with syncope due to . rence, and Aste et al. reported a recurrence of 1% at 5 years after intrinsic cardiac bradycardia are summarized in Figure 13. . pacemaker implantation among 73 patients with documented
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 40 ESC Guidelines
° °
Figure 13 Summary of indications for pacing in patients with syncope due to intrinsic cardiac bradycardia. AF = atrial fibrillation; asympt. = asymp- tomatic; AV = atrioventricular; BBB = bundle branch block; ECG = electrocardiogram; EPS = electrophysiological study; HR = heart rate; ILR = implantable loop recorder; SB = sinus bradycardia; SND = sinus node dysfunction; sympt. = symptomatic.
. persistent or intermittent documented AV block (see Supplementary . Even if the quality of evidence is moderate, there is strong con- Data Table 9). . sensus that in patients with bifascicular BBB with a positive EPS . . or documentation of paroxysmal AV block during prolonged 5.4.1.3 Bundle branch block and unexplained syncope . ECG monitoring, cardiac pacing is highly effective in preventing . The presence of bifascicular BBB suggests that the cause of syncope . syncope recurrence. The evidence of efficacy of empirical pac- may be complete heart block. Nevertheless, less than half of the . ing strategy is weak and the estimate of benefit is uncertain. . patients with bifascicular BBB and syncope will have a final diagnosis . Although syncope is not associated with an increased incidence of sud- of AV block, a similar percentage will have a final diagnosis of reflex . den death in patients with preserved cardiac function, a high incidence . syncope, and, in approximately 15%, the cause will remain unex- . of total deaths (about one-third sudden) was observed in patients with 342 . plained at the end of a complete workup. In addition, among . BBB and heart failure, previous myocardial infarction, or low ejection . 345–347 patients receiving an ILR, approximately half remained free of syn- . fraction. Indeed, the high total and sudden mortality seems to be cope for >2 years after the implantation.187,188,342,343 Conversely, . mainly related to underlying structural heart disease and ventricular . implantation of a pacemaker without documentation of AV block . tachyarrhythmias. In this latter situation, syncope is a risk factor, rather . 218 (empirical pacing) exposed patients to the risk of recurrence of syn- . than the cause, of death. Unfortunately, ventricular programmed . cope in about one-quarter of cases during long-term follow-up and . stimulation does not seem to identify these patients correctly, and the 217,344 . was unnecessary in another half. Thus, only one in four pace- . finding of inducible ventricular arrhythmia (VA) should therefore be makers will finally be appropriate. Finally, pacemaker treatment has . interpreted with caution.345,346 Therefore, an implantable cardioverter . not been proven to have a survival benefit. The above considerations . defibrillator (ICD) or a cardiac resynchronization therapy defibrillator is justify a class IIb indication in the ESC Guidelines on pacing.294 . indicated in patients with BBB, congestive heart failure, or previous 294 . To overcome the above problems, ESC Guidelines on pacing — . myocardial infarction and depressed systolic function for the preven- in patients with LVEF >35%—recommend a strategy of EPS followed . tion of SCD, but may be unable to prevent the recurrence of syncope, . by ILR if the EPS findings are unremarkable. With this strategy, a pace- . which is often due to non-arrhythmic causes such as OH or vasode- maker was implanted in approximately half of the patients and these . pressor reflex. The strategy for the management of patients with unex- . patients had syncope recurrence after pacemaker implantation in . plained syncope and BBB is summarized in Figure 14. 0–7% of cases188,217. This strategy was safe; however, this Task Force . . recognizes that in the ‘real world’, an empirical pacemaker may be . acceptable in selected patients at high risk of traumatic recurrence . 5.4.2 Syncope due to intrinsic cardiac tachyarrhythmias . (e.g. elderly patients with unpredictable syncopes) and that an individ- . Current management strategies in patients with syncope due to ual risk–benefit evaluation is warranted (Figure 14). . intrinsic cardiac tachyarrhythmia are summarized in Figure 15.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 41
Figure 14 Therapeutic algorithm for patients presenting with unexplained syncope and bundle branch block. BBB = bundle branch block; CRT-D = cardiac resynchronization therapy defibrillator; EPS = electrophysiological study; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; PM = pacemaker.
Figure 15 Choice of therapy for patients presenting with syncope due to cardiac tachyarrhythmias as the primary cause. AA = antiarrhythmic; ICD = implantable cardioverter defibrillator; SVT = supraventricular tachycardia; VT = ventricular tachycardia.
. 5.4.2.1 Paroxysmal supraventricular tachycardia . 5.4.2.2 Paroxysmal ventricular tachycardia . In patients with paroxysmal AV nodal re-entrant tachycardia, AV re- . Syncope due to torsade de pointes is not uncommon and is, in its entrant tachycardia, typical atrial flutter, and ectopic tachycardia . acquired form, the result of drugs that prolong the QT interval. . associated with syncope, catheter ablation is the first-choice treat- . Treatment is the immediate discontinuation of the suspected drug. ment. In these patients, the role of drug therapy is limited to being a . Catheter ablation or drug therapy is recommended in patients . bridge to ablation or being used when ablation has failed. In patients . with syncope due to VT in the presence or absence of structural with syncope associated with atrial fibrillation or atypical left atrial . heart disease in order to prevent syncope recurrence (Figure 15). . flutter, the decision should be individualized. . Detailed guidelines regarding antiarrhythmic drug usage in patients
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 42 ESC Guidelines
. with VT can be found in the 2015 ESC Guidelines for VA and the pre- . patients with syncope and previous myocardial infarction who have vention of SCD.46 . VT induced during EPS346 (see section 4.2.6). . An ICD is indicated in patients with syncope and depressed cardiac . In patients with preserved systolic function, the indication for ICD . function, and VT or VF without correctable cause. Although ICD . is weaker because trials have not addressed this specific issue. may not prevent syncope recurrence in these patients,31,348 it is indi- . However, when VT causes syncope, this Task Force believes that an . cated to reduce the risk of SCD (refer to the 2015 ESC Guidelines . ICD is warranted if catheter ablation and pharmacological therapy for VA and the prevention of SCD46). An ICD is also indicated in . have failed or could not be performed (Figure 15).
Treatment of syncope due to cardiac arrhythmias
Recommendations Classa Levelb
Bradycardia (intrinsic)
Cardiac pacing is indicated when there is an established relationship between syncope and symptomatic bradycardia due to:
210–212,334–338 • Sick sinus syndrome. I B
200,255,341 • Intrinsic AV block. I B
Cardiac pacing is indicated in patients with intermittent/paroxysmal intrinsic third- or second-degree AV block (including I C AF with slow ventricular conduction), although there is no documentation of a correlation between symptoms and ECGs.
Cardiac pacing should be considered when the relationship between syncope and asymptomatic sinus node dysfunction is IIa C less established.135,136,210–212,339,340
Cardiac pacing is not indicated in patients when there are reversible causes for bradycardia. III C
Bifascicular BBB
Cardiac pacing is indicated in patients with syncope, BBB, and a positive EPS or ILR-documented AV block.188,217 I B
Cardiac pacing may be considered in patients with unexplained syncope and bifascicular BBB.217,255,344 IIb B
Tachycardia
Catheter ablation is indicated in patients with syncope due to SVT or VT in order to prevent syncope recurrence.46 I B
An ICD is indicated in patients with syncope due to VT and an ejection fraction <_35%.46 I A
An ICD is indicated in patients with syncope and previous myocardial infarction who have VT induced during EPS.218 I C
An ICD should be considered in patients with an ejection fraction >35% with recurrent syncope due to VT when catheter IIa C ablation and pharmacological therapy have failed or could not be performed.46
Antiarrhythmic drug therapy, including rate-control drugs, should be considered in patients with syncope due to SVT or VT. IIa C
Additional advice and clinical perspectives • The major factors predicting the efficacy of pacing in preventing syncope recurrence are an established relationship between symptoms and bra- dycardia and the absence of associated hypotensive susceptibility (Table 8 and Supplementary Data Table 9). When this relationship is less estab- lished, or some hypotensive mechanism is present, syncope can recur in a minority of patients. • Pacing is not indicated in unexplained syncope without evidence of any conduction disturbance. • Less than half of the patients with bifascicular BBB and syncope have a final diagnosis of cardiac syncope, albeit the probability is different among thetypes of BBB. We recommend conducting any useful investigation (e.g. CSM, EPS, or ILR) to provoke/document the mechanism of syncope before deciding to implant a pacemaker or selecting the correct therapy. • Elderly patients with bifascicular BBB and unexplained syncope after a reasonable workup might benefit from empirical pacemaker implantation, especially if syncope is unpredictable (with no or short prodromes) or has occurred in the supine position or during effort. • When indicated, ICD prevents SCD but it may be unable to prevent syncope due to VT recurrence.31,348 Thus, when syncope is due to VT (including when the diagnosis is established by the induction of VT during EPS), catheter ablation should be always attempted when feasible in addition to ICD implantation.
AF = atrial fibrillation; AV = atrioventricular; BBB = bundle branch block; CSM = carotid sinus massage; ECG = electrocardiogram; EPS = electrophysiological study; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; SCD = sudden cardiac death; SVT = supraventricular tachycardia; VT = ventricular tachycardia. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 43
. 5.5 Treatment of syncope secondary to . 5.6.2 Left ventricular systolic dysfunction . The benefit of an ICD to reduce the risk of death is established. Thus, structural cardiac, cardiopulmonary, and . great vessel disease . patients with unexplained syncope who have an established ICD indi- . cation per current Guidelines46 must receive an ICD before, and Cardiac syncope is diagnosed when syncope presents in patients with . . independently of, the evaluation of the mechanism of syncope, even if severe aortic stenosis, acute myocardial infarction/ischaemia, HCM, . . the mechanism of syncope is unknown or uncertain at the end of a cardiac masses (atrial myxoma, ball thrombus, etc.), pericardial dis- . . complete workup. While this strategy may help to prolong life, ease/tamponade, congenital anomalies of the coronary arteries, pros- . . patients often remain at risk of recurrent syncope, implying a need thetic valve dysfunction, pulmonary embolus, acute aortic dissection, . . for precise identification of the mechanism of syncope and specific and pulmonary hypertension (see section 4.1.1). Structural cardiac or . . treatment when possible. cardiopulmonary disease can be present in some patients with syn- . . Few data exist concerning the prevalence and the prognostic impli- cope, and its incidence increases in older patients. The mere presence . . cations of unexplained syncope in unselected patients with left ven- of heart disease does not imply that syncope is related to the underly- . . tricular dysfunction or non-ischaemic dilated cardiomyopathy with ing cardiac disorder. Some of these patients have typical reflex syn- . cope; in others, such as those with inferior myocardial infarction or aortic stenosis, the underlying cardiac disease may play a role in trig- Implantable cardioverter defibrillator indications in gering or potentiating a reflex mechanism, and—finally—the underly- patients with unexplained syncopea and left ventricular ing cardiac disease may be the substrate for conduction disturbances, systolic dysfunction supraventricular arrhythmia, or VA that causes syncope. Recommendations Classb Levelc Even in the absence of specific trials, there is strong consensus that with syncope secondary to structural cardiac disease, the ICD therapy is recommended to reduce goal of treatment is not only to prevent syncopal recurrence, but SCD in patients with symptomatic heart fail- ure (NYHA class II–III) and LVEF <_35% after to treat the underlying disease and decrease the risk of death. I A >_3 months of optimal medical therapy, who 5.6 Treatment of unexplained syncope in are expected to survive >_1 year with good 46 patients at high risk of sudden cardiac functional status. death An ICD should be considered in patients a The underlying clinical situation is that of a patient being evaluated for with unexplained syncope with systolic ICD implantation because they are affected by syncope(s) supposedly impairment, but without a current indication IIa C due to transient self-terminating ventricular tachyarrhythmias (fast VT or for ICD, to reduce the risk of sudden 27,28,359,360 VF), which have not yet been documented because of their short dura- death. 349 tion. Syncope due to documented VT/VF is outside the scope of this Instead of an ICD, an ILR may be considered section; please refer to section 5.4.2. General guidance may be sought in in patients with recurrent episodes of unex- 46 IIb C the 2015 ESC Guidelines for VA and the prevention of SCD. plained syncopea with systolic impairment, but without a current indication for ICD. 5.6.1 Definition In general, a history of syncope in patients with structural heart Additional advice and clinical perspectives disease or inheritable arrhythmia syndromes is associated with a • The presence of syncope increases mortality regardless of its 348 two- to four-fold increased risk of death,348,350–353 but varies cause. Thus, syncope is a risk factor for life-threatening between specific conditions.354–356 Moreover, there have been events. very few studies on ICDs in patients with syncope associated with • The decision to implant an ICD or to complete the left ventricular dysfunction,31,348 cardiomyopathy, or inheritable investigation (e.g. ILR implantation) in patients with unex- arrhythmia syndromes.357 In these Guidelines, we complement plained syncope depends on a global clinical evaluation previous ESC Guidelines for VA and the prevention of SCD46 by of the patient’s conditions, the potential benefit and harm providing a precise definition of unexplained syncope, and making of such therapy, and the presence of other risk factors recommendations for its investigation and management in differ- for SCD. ent clinical settings.
• For this section, ‘unexplained syncope‘ is defined as syncope that ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; does not meet any class I diagnostic criterion defined in the LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; tables of recommendations in section 4. In the presence of clini- SCD = sudden cardiac death. a cal features described in this section, unexplained syncope is con- Unexplained syncope is defined as syncope that does not meet a class I diagnos- tic criterion defined in the tables of recommendations in section 4. In the pres- sidered a ‘suspected arrhythmic syncope’. ence of clinical features described in this section, unexplained syncope is considered a risk factor for ventricular tachyarrhythmias. When the mechanism of syncope is non-arrhythmic, the manage- bClass of recommendation. ment of patients at high risk of SCD is the same as for patients with- cLevel of evidence. out syncope.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 44 ESC Guidelines
. less severe systolic impairment who do not meet the current indica- . 5.6.4 Arrhythmogenic right ventricular tion for ICD.358 Data from observational studies in selected cohorts . cardiomyopathy . show a high rate of occurrence of ventricular arrhythmias, ICD dis- . Although limited and diverse, current data suggest that unexplained syn- charge, and death in patients with a history of unexplained syncope . cope is a marker of arrhythmic risk in patients with ARVC.46,351,362,363 . but, owing to a lack of control groups, are unable to show the benefit . The decision to implant an ICD should take into account the other of an ICD.27,28,359,360 This Task Force believes that an ICD should be . known risk factors for arrhythmic events46:frequentnon-sustainedVT, . considered in patients with unexplained syncope with systolic impair- . family history of premature sudden death, extensive right ventricular ment but without a current indication for ICD to reduce the risk of . disease, marked QRS prolongation, late gadolinium enhancement on . sudden death. . magnetic resonance imaging (MRI) (including left ventricular involve- . 46 . ment), left ventricular dysfunction, and VT induction during EPS. . 5.6.3 Hypertrophic cardiomyopathy Unexplained syncope is an independent predictor for SCD and appropriate ICD discharge. In a systematic review, the average haz- Implantable cardioverter defibrillator indications in a ard ratio of unexplained syncope (irrespective of definition) was 2.68 patients with unexplained syncope and arrhythmogenic right ventricular cardiomyopathy (95% CI 0.97–4.38).361 In the largest multicentre study to date (>3600 patients with HCM), syncope was an independent predictor b c of the composite of SCD and ICD discharge (hazard ratio 2.05, 95% Recommendations Class Level 350 CI 1.48–2.82). A prophylactic ICD is appropriate in individuals ICD implantation may be considered in with other features indicative of a high risk of SCD that are used to patients with ARVC and a history of unex- IIb C 245 estimate the 5-year risk of SCD using the HCM Risk-SCD model ; plained syncope.a,46 they include: age, family history of SCD, maximum left ventricular wall thickness, left atrial diameter, and non-sustained VT. Instead of an ICD, an ILR should be consid- ered in patients with recurrent episodes of unexplained syncope who are at low risk of IIa C Implantable cardioverter defibrillator indications in SCD, based on a multiparametric analysis a patients with unexplained syncope and hypertrophic that takes into account the other known cardiomyopathy risk factors for SCD.
b c Recommendations Class Level ARVC = arrhythmogenic right ventricular cardiomyopathy; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; SCD = sudden car- It is recommended that decisions for ICD diac death. implantation in patients with unexplained aUnexplained (or uncertain) syncope is defined any syncope that does not meet I B syncopea are made according to the ESC class I diagnostic criteria defined in the tables of recommendations in section 4. In d,245 the presence of clinical features described in this section, unexplained syncope is HCM Risk-SCD score. considered a risk factor for ventricular tachyarrhythmias. bClass of recommendation. Instead of an ICD, an ILR should be consid- cLevel of evidence. ered in patients with recurrent episodes of unexplained syncopea who are at low risk of IIa C SCD, according to the HCM Risk-SCD score.d,245 5.6.5 Patients with inheritable arrhythmogenic disorders 5.6.5.1 Long QT syndrome Additional advice and clinical perspectives Syncopal events in long QT syndrome (LQTS) are associated with an The decision to implant an ICD or to complete the investigation increased risk of subsequent cardiac arrest. The annual rate of SCD in (e.g. ILR implantation) in patients with unexplained syncope patients with untreated LQTS is around 0.9% overall and 5% for those depends on a global clinical evaluation of the patient’s condition, with syncope.352,364 Beta-blocker therapy substantially reduces the risk the potential benefit and harm of such therapy, and the presence of syncope and SCD, but presentation with cardiac arrest and recur- of other risk factors for SCD. rent syncope during beta-blocker therapy is associated with the same risk of fatal events as in untreated patients.46 For this reason, ICD treat- ESC = European Society of Cardiology; HCM = hypertrophic cardiomyopathy; ment should be considered in patients with LQTS and recurrent unex- ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; plained syncope despite beta-blocker therapy, especially in cases of SCD = sudden cardiac death. aUnexplained syncope is defined as syncope that does not meet the class I diag- good treatment compliance, in the absence of precipitating factors, nostic criterion defined in the tables of recommendations in section 4. In the and in LQT2 and LQT3 syndromes. Left cardiac sympathetic denerva- presence of clinical features described in this section, unexplained syncope is con- tion should also be considered in this situation, particularly in LQT1.46 sidered a risk factor for ventricular tachyarrhythmias. bClass of recommendation. cLevel of evidence. 5.6.5.2 Brugada syndrome d A web-based calculator of the HCM risk score can be found at: http://www. A history of syncope may increase the risk of arrhythmic events up to doc2do.com/hcm/webHCM.html. It can also be found in the ESC Pocket Guidelines App found in all app stores. two- to three-fold compared with that in asymptomatic patients. In the largest registry (1029 patients), the incidence of arrhythmic events
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 45
. (sustained VT or VF, appropriate ICD therapy, or sudden death) in . risk factors for arrhythmic events, including spontaneous type 1 Brugada . patients with Brugada syndrome was 7.7% per year in those with a . ECG pattern, family history of sudden death, VF inducibility with one or history of sudden cardiac arrest, 1.9% per year with syncope, and . two ventricular premature beats during EPS, fractionated QRS, early 353 . 0.5%peryearinasymptomaticpatients. However, in a second . repolarization in the peripheral leads, increased Tpeak–Tend interval, and study, the rate of appropriate ICD shocks was similar in asymptomatic . long PR interval.220,367–371 A drug-induced type 1 ECG pattern has a . patients and in those with syncope, a difference possibly explained by . lower risk of sudden death than a spontaneous type 1 response. patient selection and a high rate of non-arrhythmic syncope.355 .
Implantable cardioverter defibrillator indications in Implantable cardioverter defibrillator indications in patients with unexplained syncopea and Brugada patients with unexplained syncopea and long QT syndrome syndrome
Recommendations Classb Levelc Recommendations Classb Levelc ICD implantation should be considered in ICD implantation in addition to beta-blockers patients with a spontaneous diagnostic IIa C should be considered in LQTS patients who type 1 ECG pattern and a history of a IIa B experience unexplained syncope while unexplained syncope.a,46,353,355,365,366 receiving an adequate dose of beta-blockers.46 Instead of an ICD, an ILR should be consid- Left cardiac sympathetic denervation should ered in patients with recurrent episodes of be considered in patients with symptomatic unexplained syncopea who are at low risk of IIa C LQTS when: SCD, based on a multiparametric analysis (1) beta-blockers are not effective, not tol- that takes into account the other known erated, or are contraindicated; IIa C risk factors for SCD. (2) ICD therapy is contraindicated or refused; or ECG = electrocardiogram; ICD = implantable cardioverter defibrillator; ILR = (3) when patients on beta-blockers with an implantable loop recorder; SCD = sudden cardiac death. a ICD experience multiple shocks.46 Unexplained (or uncertain) syncope is defined as any syncope that does not meet the class I diagnostic criteria defined in section 4. In the presence of clinical Instead of an ICD, an ILR should be consid- features described in this section, unexplained syncope is considered a risk factor for ventricular tachyarrhythmias. ered in patients with recurrent episodes of bClass of recommendation. a unexplained syncope who are at low risk of cLevel of evidence. IIa C SCD based on a multiparametric analysis that takes into account the other known risk factors for SCD. 5.6.5.3 Other forms Additional advice Due to a lack of studies examining unexplained syncope in other forms Beta-blockers are recommended in all patients with a clinical diagno- of inheritable arrhythmic diseases such as catecholaminergic polymor- sis of LQTS, with the possible exception of those with LQTS3 form. phic VT, early repolarization syndrome, and short QT syndrome, this Task Force is unable to give specific recommendations for the investi- ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; gation and treatment of unexplained syncope. For further information LQTS = long QT syndrome; SCD = sudden cardiac death. 46 aUnexplained (or uncertain) syncope is defined as any syncope that does not refer to the 2015 ESC Guidelines for VA and the prevention of SCD. meet class I diagnostic criteria defined in the tables of recommendations in sec- tion 4. In the presence of clinical features described in this section, unexplained syncope is considered a risk factor for ventricular tachyarrhythmias. bClass of recommendation. 6. Special issues cLevel of evidence. 6.1 Syncope in patients with comorbidity and frailty On balance, this Task Force believes that it is reasonable to con- The approach to the assessment and management of an older patient sider an ICD in the case of unexplained syncope. New studies356,365 with syncope is similar to that of other age groups; however, there published after the 2015 ESC Guidelines for VA and the prevention of are a number of additional features pertinent to age-related comor- 372–374 SCD46 showed that non-arrhythmic syncope is frequent in Brugada bidity and frailty that warrant special attention. syndrome and appears to be more benign; thus, ICD should be avoided in patients with non-arrhythmic syncope that is established 6.1.1 Comorbidity and polypharmacy according to the definition reported in this section. ILR is increasingly Comorbidity influences the diagnosis of syncope and management used in doubtful cases to exclude a VA as the cause of syncope.365,366 decisions.33,375 Older patients frequently have abnormal findings on The final decision to implant an ICD in patients with Brugada syn- more than one investigation and may have more than one possible drome and unexplained syncope should also take into account other cause of syncope.372,374,376 Conversely, coincidental findings of
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 46 ESC Guidelines
377 . cardiovascular diagnoses such as aortic stenosis or atrial fibrillation . 6.1.3 Cognitive assessment and physical performance tests may not necessarily be the attributable cause of events.378–380 . Age-related memory impairment or more established forms of cog- . The prescription of polypharmacy, cardiovascular medications, and . nitive impairment are frequently associated with poor recall and psychotropic (neuroleptics and antidepressants) and dopaminergic . therefore the lack of an accurate history of events. In such circum- 381–385 . drugs also increases the risk of syncope and falls. Conversely, . stances, details of prodromal symptoms, whether or not LOC the discontinuation or reduction of hypotensive therapy reduces such . occurred, and symptoms after the event may be unre- 260 . 373,389,391–394 risk. Negative dromotropic and chronotropic medications should . liable. Cognitive assessment to inform the accuracy of be carefully evaluated in older patients presenting with syncope or falls. . historical data, and general physical assessment to identify comorbid . Focal neurological events can occasionally occur due to hypoten- . disorders that influence diagnosis and response to treatments (such sion and syncope, even in patients without significant carotid artery . as Parkinson’s disease, gait and balance abnormalities, previous . stenosis (so called ‘hypotensive TIA’). Although these neurological . stroke, and polyneuropathies, etc.), are recommended. events occur in only 6% of patients with recurrent syncope, their mis- . . diagnosis is particularly important because they may lead to a lowering . Despite the lack of large controlled trials and an overall modest of BP with antihypertensive medications (e.g. if focal neurology is mis- . quality of studies, there is strong consensus that the assessment . takenly attributed to vascular pathology rather than hypotension), and . of older patients with syncope or unexplained falls may require 386 . to a further increase of the risk of syncope and neurologic events. . cognitive assessment and physical performance tests in addition . to syncope evaluation. Further research is likely to have an . Despite the lack of large controlled trials and an overall mod- . important impact on our confidence in the estimate of effect. est quality of studies, there is strong consensus that reduction . or discontinuation of hypotensive drugs and psychotropic drugs Syncope in patients with comorbidity and frailty clearly outweighs the undesirable effects (e.g. complications) of high BP. Further research is likely to have an important a b impact on our confidence in the estimate of effect. Recommendations Class Level Multifactorial evaluation and intervention is recommended in older patients because more I B 6.1.2 Falls than one possible cause for syncope and unex- 33,372–374,376–380 Syncopal events may be unwitnessed in over half of older patients plained fall may be present. meaning that collateral histories may not available, which makes discrim- Cognitive assessment and physical perform- 387 ination between falls and syncope challenging. If unwitnessed falls are ance tests are indicated in older patients with I C not due to mechanical slips or trips (i.e. are unexplained or non- syncope or unexplained fall.373,389,391–394 accidental), it is likely that the patient experienced a syncopal event and displayed lack of awareness for LOC (Figure 16).388,389 Management of Modification or discontinuation of possible culprit 191,194,390 medications, particularly hypotensive drugs and falls in such circumstances is the same as that for syncope. IIa B psychotropic drugs, should be considered in older 260,381–385 Despite the lack of controlled trials and an overall modest patients with syncope or unexplained fall.
quality of studies, there is strong consensus that the manage- In patients with unexplained fall, the same ment of unexplained falls should be the same as that for unex- assessment as for unexplained syncope should IIa C plained syncope. be considered.191,194,387–390
Additional advice and clinical perspectives • In some frail elderly patients, the rigour of assessment will depend on compliance with tests and on prognosis. Otherwise, the evalu- ation of mobile, non-frail, cognitively normal older adults must be performed as for younger individuals.393,395 • Orthostatic BP measurements, CSM, and tilt testing are well tol- erated, even in the frail elderly with cognitive impairment.96,396,397 • Not infrequently, patients who present with unexplained falls— although orthostatic BP measurements, CSM, and tilt testing repro- duce syncope—may deny TLOC, thus demonstrating amnesia for TLOC.388,389 • Failure of orthostatic BP to stabilize is present in up to 40% of community-dwelling people >80 years of age when BP is meas- ured using phasic BP technology.398 Such failure of systolic BP to stabilize is a risk factor for subsequent falls and syncope. • In the absence of a witness account, the differential diagnosis between falls, epilepsy, TIA, and syncope may be difficult. Figure 16 Flow diagram for the identification of unexplained falls. BP = blood pressure; CSM = carotid sinus massage; TIA = transient ischaemic attack; TLOC = transient loss of consciousness. aClass of recommendation. bLevel of evidence.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 47
. 6.2 Syncope in paediatric patients . • Children with a history suggesting VVS, a normal ECG, and no . family history of arrhythmia should not undergo further cardiac 6.2.1 Diagnostic evaluation . . investigations. Diagnostic evaluation in paediatric patients is similar to that in adults. . . The cornerstone of therapy for young patients with reflex syn- 399 . • Two specific conditions occur in early childhood: . cope includes education and reassurance. . • Infantile reflex syncopal attacks (also called pallid breath-holding . . spells or reflex anoxic seizures), elicited by a brief unpleasant . stimulus, caused by vagally mediated cardiac inhibition. . 7. Psychogenic transient loss of Cyanotic breath-holding spells, characterized by stopping . • . consciousness and its evaluation breathing during crying, leading to cyanosis and usually . TLOC. . . In psychogenic TLOC there is no gross somatic brain dysfunction, . Careful taking of personal and family history and a standard . but the attacks fulfil the criteria for TLOC (see section 3.1). There ECG are the most important methods of distinguishing benign . are two types: PPS and PNES. In PPS movements are absent, so . reflex syncope (also including reflex anoxic seizure or breath- . PPS resembles syncope or longer-lasting LOC, whereas in PNES holding spells) from other causes. If the family history is positive, . impressive limb movements mean the attacks resemble epileptic . genetic causes of electrical disease of the heart should be consid- . seizures. PPS and PNES differ pathophysiologically from the ered first. Some children with reflex syncope also have a positive . TLOC forms that they resemble: in PPS, BP and HR are normal or 400 . family history. Tilt testing seems to have high false-negative and . high rather than low, and the EEG is normal instead of showing false-positive rates and should be used with caution for the pri- . the slowing or flattening typical of syncope; in contrast to epileptic . mary identification of reflex syncope. Since tilt protocols com- . seizures, the EEG in PNES shows no epileptiform brain activity monly used in adults may lack specificity in teenagers, in one study, . during an attack.9,116 . a shorter tilt test duration of 10 min at 60 or 70 degrees was used . The frequency of PPS and PNES probably depends on the 401 . and showed a specificity of >85%. . setting. The rate of PPS varies from 1% of patients referred to . 94 In young patients, syncope can rarely be the initial manifestation of . general syncope clinics to 8% of patients referred to specialist . 116 unusual but life-threatening conditions such as LQTS, Kearns–Sayre . neurological clinics, but PPS is probably insufficiently syndrome (external ophthalmoplegia and progressive heart block), . recognized.154 . Brugada syndrome, catecholaminergic polymorphic VT, . Wolff-Parkinson-White syndrome, ARVC, HCM, pulmonary arterial . . 7.1 Diagnosis hypertension, myocarditis, arrhythmia after repaired congenital heart . 7.1.1 Historical criteria for attacks . disease, and anomalous origin of a coronary artery. . The presence of a psychological trauma is not a prerequisite for a Some aspects of the history can suggest a cardiac origin, and . diagnosis of conversion. The diagnosis of PPS rests on positive clues . should prompt cardiac evaluation. . taken from the patient’s history and from documenting normal EEG . • Family history: premature SCD at age <40 years and/or familial . results, HR, or BP during an attack. History taking in PPS usually . 116,154,403 heart disease. . reveals a combination of the following features : • Known or suspected heart disease. . . (1) In most cases, the duration of PPS is as short as in syncope, but a • Event triggers: loud noise, fright, and/or extreme emotional . . much longer duration is a useful diagnostic finding: patients may lie stress. . • Syncope during exercise, including swimming. . immobile on the floor for 15–30 min. . • Syncope without prodromes, while supine or sleeping, or pre- . (2) The eyes are usually open in epileptic seizures and syncope but are ceded by chest pain or palpitations. . usually closed in psychogenic TLOC. . . (3) The attack frequency is high, with several attacks occurring over a 6.2.2. Therapy . week or in a day. . The therapeutic approach is the same as in adults. However, it should . (4) There is usually no recognisable trigger, and no sweating, pallor, or be stressed that the effectiveness of pharmacological agents and tilt . nausea beforehand. . training for recurrent reflex syncope is undetermined in the absence . (5) Injury does not exclude PNES or PPS. of well-designed paediatric trials. Furthermore, even in the presence . . These features should occur together in most attacks. The pres- of VVS with prolonged asystole, pacemakers should be avoided due . . ence of another pattern of features suggesting a true syncope type, to the relatively transient and benign nature of the syndrome.402 . . usually VVS, does not argue against a diagnosis of PPS. In summary, the key points for the evaluation of syncope in paedi- . atrics are as follows: . . . 7.1.2 Documentation of key features during an attack • Syncope in childhood is common, the majority being of reflex . The following features are relevant during an attack: origin, with only a minority having a potentially life-threatening . . cause. . • Video recording or clinical observation, including provocation of • Discriminating benign from serious causes is made primarily by . an attack during tilt testing. Primary features: sleep-like body posi- history, physical examination, and ECG results. . tion with closed eyes and lack of response to speech or touch, if
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 48 ESC Guidelines
. tested. Secondary features: subtle signs incompatible with LOC . 8. Neurological causes and mimics such as eyelid flicker, eyeball movements, swallowing, intact . . muscle tone, normal movements absent in true unconsciousness, . of syncope and resistance to eye opening. . . This section discusses neurological disorders causing syncope or • BP: normal or elevated during TLOC. . EEG: normal waking eye-closed EEG pattern, i.e. usually with . resembling it, and tests to be performed in patients with syncope. • . alpha activity, during TLOC. . . 8.1 Clinical conditions The gold standard for PPS is documenting an attack with a home . . 8.1.1 Autonomic failure video recorder or with a tilt testing during which BP, HR, and EEG . 116,204,404 . Neurological evaluation should be considered in OH due to auto- are normal. The gold standard for PNES is documenting an . 204,404 . nomic failure. Warning signs are early impotence, disturbed micturi- attack with video-EEG monitoring. . . tion, hyposmia, rapid eye movement, sleep behaviour . disorders,408,409 Parkinsonism, ataxia, cognitive impairment, and sen- 7.1.2.1 Management of psychogenic pseudosyncope . . sory deficits. A multidisciplinary approach may be required in secon- Announcing a psychological diagnosis to patients may be considered . . dary autonomic failure and in drug-induced OH, depending on the difficult, but is necessary for reasons of honesty and as the first step of . 404 . underlying disease. treatment. It should be done by the somatic specialist who diagnoses . PPS.116,404 Important aspects are to assure patients that they are taken . . seriously and that attacks are as involuntary as syncope or an epileptic . 8.1.2 Epilepsy and ictal asystole . seizure. Acceptance of the diagnosis by patients may be critical for ther- . Table 10 provides a number of clues that aid the differentiation of . 9,50,410,411 405 . syncope from epileptic seizures. Epilepsy and syncope apy. In one observational study, communicating and explaining the . diagnosis resulted in an immediate reduction of attack frequency, with . may evoke one another on rare occasions, resulting in epileptic . seizures triggering syncope as well as syncope triggering an epilep- 39% of patients being asymptomatic during a mean follow-up period of . 4 years. Some advice on how to inform the patient is provided in Web . tic seizure. The first form concerns ictal asystole. Whereas approx- . imately 90% of all epileptic seizures are accompanied by Practical Instructions section 10: European Society of Cardiology information . sheet for patients affected by psychogenic pseudosyncope. . tachycardia, ictal bradycardia and asystole occur in 0.3–0.5% of . 412,413 Cognitive behavioural therapy is the usual treatment of PNES and . seizures. Bradycardia precedes asystole and AV block may . occur, resembling the ECG pattern of reflex syncope.412,414 PPS, if attacks remain present after explanation. One pilot random- . ized treatment trial, conducted in PNES,406 showed that psychologi- . Epileptic asystole occurs during partial complex seizures, not dur- . ing generalized seizures. Epileptic asystole occurs in only a fraction cal therapy provided more attack reduction than no treatment or . treatment with sertraline. There are currently no trials on PPS. . of the seizures of one person, and then occurs after a variable . 415,416 . interval of 5–100 s from seizure onset. If asystole lasts for . 416 . more than about 8 s, syncope ensues. A typical history is for a . partial complex seizure to progress as usual for that patient, and Diagnosis and management of psychogenic . . then the patient suddenly falls flaccidly, with or without brief myo- pseudosyncope . 416,417 . clonic jerking. Ictal bradycardia, asystole, and ictal AV block . are likely self-terminating,412 and are due to vagal activation Recommendations Classa Levelb . . brought about by the seizure. Cessation of cortical activity due to . Diagnosis . syncopal cerebral hypoperfusion will end the seizure. Therapy . requires anti-epileptic drugs and possibly a pacemaker.418 The recording of spontaneous attacks with . . Ictal asystole is probably not involved in sudden death in epilepsy, a video by an eyewitness should be consid- IIa C . as this typically occurs in patients after unwitnessed nocturnal 116,154 . ered for diagnosis of PPS. . generalized tonic-clonic seizures, i.e. another type of epi- . 414,419 Tilt testing, preferably with concurrent EEG . lepsy. Note that most cases of sudden cardiac arrest in recording and video monitoring, may be IIb C . patients with epilepsy are due to cardiovascular disease and not to . 420 considered for diagnosis of PPS.116,403,407 . ictal asystole. . . The second form concerns a syncopal epileptic seizure. Management . Hypoxia can trigger epileptic seizures.208,421 Such syncopal epilep- . Doctors who diagnose PPS should present . tic seizures have been described in infants with reflex syncope IIa C . 116,404 . or cyanotic breath-holding spells. A typical syncopal spell the diagnosis of PPS to the patient. . . suddenly transforms into prolonged clonic movements that Cognitive behavioural therapy may be con- . last for minutes; note that shorter epileptic seizures may remain sidered in the treatment of PPS if attacks . IIb C . unnoticed. persist after explanation. . . . 8.1.3 Cerebrovascular disorders EEG = electroencephalogram; PPS = psychogenic pseudosyncope. . a . In general, a TIA concerns a focal neurological deficit without LOC, Class of recommendation. . bLevel of evidence. . and syncope the opposite. Subclavian steal refers to the rerouting of . blood flow to the arm through the vertebral artery due to proximal
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 49
Table 10 Differentiating syncope from epileptic seizures9,50,410,411
Clinical feature Syncope Epileptic seizures
Useful features
Presence of trigger Very often Rare
Nature of trigger Differs between types: pain, standing, emo- Flashing lights is best known; also range of rare tions for VVS; specific trigger for situational triggers syncope; standing for OH
Prodromes Often presyncope (autonomic activation in Epileptic aura: repetitive, specific for each patient. reflex syncope, light-headedness in OH, palpi- Includes de´j avu. Rising sensation in the abdomen tations in cardiac syncope) (epigastric aura) and/or an unusual unpleasant smell
Detailed characteristics of • <10, irregular in amplitude, asynchronous, • 20–100, synchronous, symmetrical, hemilateral myoclonus asymmetrical • The onset mostly coincides with LOC • Starts after the onset of LOC • Clear long-lasting automatisms as chewing or lip smacking at the mouth
Tongue bite Rare, tip of tongue Side of tongue (rarely bilateral)
Duration of restoration of 10–30 seconds May be many minutes consciousness
Confusion after attack No understanding of situation for <10 seconds Memory deficit, i.e. repeated questions without in most syncope, full alertness and awareness imprinting for many minutes afterwards
Features of limited utility
Incontinence Not uncommon Common
Presence of myoclonus (see below Very often 60%, dependent on accuracy of observation for nature of myoclonus)
Eyes open during LOC Frequent Nearly always
Fatigue and sleep afterwards Common, particularly in children Very common
Blue face Rare Fairly often
LOC = loss of consciousness; OH = orthostatic hypotension; VVS = vasovagal syncope.
. stenosis or occlusion of the subclavian artery. A TIA may occur when . A TIA of the vertebrobasilar system can cause LOC, but there are . flow through the vertebral artery cannot supply both the arm and . always focal signs, usually limb weakness, gait and limb ataxia, vertigo, part of the brain during forceful use of the arm. Steal most often . diplopia, nystagmus, dysarthria, and oropharyngeal dysfunction. . affects the left side. When detected with ultrasound, steal is asympto- . Fewer than 1% of patients with vertebrobasilar ischaemia present matic in 64% of cases.422 A TIA is likely due to steal only when it is . with a single presenting symptom.425 . vertebrobasilar (see below) and associated with exercise of one arm. . There are no reliable reports of isolated LOC without focal neuro- . . logical symptoms and signs in subclavian steal. . 8.1.4 Migraine A TIA related to a carotid artery does not usually cause TLOC. An . Syncope, presumable VVS, and orthostatic intolerance occur more . exception concerns orthostatic TIAs, concerning a combination of . often in patients with migraine, who have a higher lifetime prevalence . 426 multiple stenoses of cerebral arteries and OH. This may rarely result . of syncope and often frequent syncope. In migraineurs, syncope in repetitive, orthostatic, short-lasting, and stereotyped TIAs.423,424 . and migraine attacks rarely occur simultaneously.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 50 ESC Guidelines
. 8.1.5 Cataplexy . 8.2.3 Neurovascular studies . Cataplexy concerns paresis or paralysis triggered by emotions, usu- . No studies suggest that carotid Doppler ultrasonography is valuable ally laughter, but also by a range of other triggers.427 Patients are con- . in patients with typical syncope. . scious even when considered unconscious by eyewitnesses, and . there is no amnesia. Cataplexy is a key feature of narcolepsy; other . . 8.2.4 Blood tests cardinal symptoms are excessive daytime sleepiness, sleep-onset . paralysis, and hypnagogic hallucinations. Cataplexy may be mistaken . An acute or subacute onset of multidomain autonomic failure sug- . gests a paraneoplastic or autoimmune cause. Screening for specific for syncope, but also for PPS: a partial awareness of events may be . present in PPS, and the falls of cataplexy are partly controlled because . paraneoplastic antibodies is recommended: the most common para- . neoplastic antibodies are anti-Hu, while others are anti-Purkinje cell paralysis need not be immediately complete. . . cytoplasmic autoantibody type 2 and anti-collapsin response media- . tor protein 5.431 Seropositivity for any of the above-mentioned anti- 8.1.6 Drop attacks . . bodies may therefore prompt further investigation for occult The term drop attacks is confusing as it is variably used for . . malignancy (e.g. whole-body fluorodeoxyglucose-positron emission Menie`re’s disease, atonic epileptic seizures, and unexplained . . tomography).432 falls.387 A specific condition also labelled drop attacks concerns . . Seropositivity for antiganglionic acetylcholine receptor middle-aged women (rarely men) who suddenly find themselves . . antibodies is the serological hallmark of autoimmune autonomic falling.428 They usually remember hitting the floor and can stand . . ganglionopathy.433,434 up immediately afterwards.
Neurological evaluation Neurological tests
Recommendations Classa Levelb Recommendations Classa Levelb Neurological evaluation is indicated Brain MRI is recommended if neurological when syncope is due to autonomic fail- I C examination indicates Parkinsonism, ataxia, I C ure to evaluate the underlying disease. or cognitive impairment. Neurological evaluation is indicated in Screening for paraneoplastic antibodies and patients in whom TLOC is suspected to I C antiganglionic acetylcholine receptor anti- be epilepsy. bodies is recommended in cases of acute or I B subacute onset of multidomain autonomic TLOC = transient loss of consciousness. failure.432,433 aClass of recommendation. b Level of evidence. EEG, ultrasound of neck arteries, and com- puted tomography or magnetic resonance III B imaging of the brain are not indicated in 8.2 Neurological tests patients with syncope.178,435–440 A schematic comprehensive figure of neurological tests used for Additional advice and clinical perspectives autonomic failure is shown in Figure 17. Seropositivity for any paraneoplastic antibody or for antigan- glionic acetylcholine receptor antibodies should prompt further 8.2.1 Electroencephalography investigations for occult malignancy. The results of interictal EEGs are normal in syncope.410,430 An interic- tal normal EEG cannot rule out epilepsy and the EEG in epilepsy EEG = electroencephalogram; MRI = magnetic resonance imaging. a must always be interpreted in a clinical context. An EEG is not rec- Class of recommendation. bLevel of evidence. ommended when syncope is the most likely cause of TLOC, but it is when epilepsy is the likely cause or when clinical data are equivocal. The EEG is also useful to establish PPS, if recorded during a provoked attack. 9. Organizational aspects
8.2.2 Brain computed tomography and magnetic 9.1 Syncope (transient loss of resonance imaging consciousness) management unit Computed tomography and MRI in uncomplicated syncope should Since the publication of the 2009 ECS Guidelines, the EHRA Task be avoided. If neurological examination points out Parkinsonism, Force has published a further position statement on the rationale and ataxia, or cognitive impairment, MRI is recommended. In cases of requirement for syncope units.63 The position paper offers a prag- contraindication for MRI, computed tomography is recommended to matic approach to the rationale and requirement for a syncope unit. exclude brain lesions. It is addressed to physicians and others in administration who are
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 51
Figure 17 Diagnostic work-up of cardiovascular autonomic failure (adapted from Fanciulli et al.429). CNS = central nervous system; CRMP-5 = collapsin response mediator protein 5; DAT = dopamine active transporter; HbA1c = haemoglobin A1c; HIV = human immunodeficiency virus; 123I- MIBG = 123I-metaiodobenzylguanidine; MRI = magnetic resonance imaging; PCA-2 = Purkinje cell cytoplasmic autoantibody type 2; SPECT = single- photon emission computed tomography; SS-A = Sjogren’s syndrome-associated antigen A; SS-B = Sjogren’s syndrome-associated antigen B.
Table 11 Key components of a syncope unit
• The syncope unit should take the lead in service delivery for syncope, and in education and training of healthcare professionals who encounter syncope. • The syncope unit should be led by a clinician with specific knowledge of TLOC and additional necessary team members (i.e. clinical nurse special- ist) depending on the local model of service delivery.
• The syncope unit should provide minimum core treatments for reflex syncope and OH, and treatments or preferential access for cardiac syn- cope, falls, psychogenic pseudosyncope, and epilepsy.
• Referrals should be directly from family practitioners, EDs, in-hospital and out-hospital services, or self-referral depending on the risk stratifica- tion of referrals. Fast-track access, with a separate waiting list and scheduled follow-up visits, should be recommended.
• Syncope units should employ quality indicators, process indicators, and desirable outcome targets.
ED = emergency department; OH = orthostatic hypotension; TLOC = transient loss of consciousness.
interested in establishing a syncope unit in their hospital so that they . 9.1.1 Definition of a syncope unit . can meet the standards proposed by the ESC, the EHRA, and the . A syncope unit is a facility featuring a standardized approach to the Heart Rhythm Society. The following is the context and evidence for . diagnosis and management of TLOC and related symptoms, with . recommendations regarding syncope units (Table 11). . dedicated staff and access to appropriate diagnostics and therapies.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 52 ESC Guidelines
. 9.1.2 Definition of syncope specialist . scientific or economic scrutiny, the consensus is that a dedicated . service (a syncope unit) affords better management of TLOC, from The syncope specialist is defined as one who has responsibility for . the comprehensive management of the patient from risk stratification . risk stratification to diagnosis, therapy, and follow-up, and better edu- . to diagnosis, therapy, and follow-up, through a standardized protocol. . cation and training of stakeholders. Further research is likely to have A syncope specialist is a physician who has sufficient knowledge of . an important impact on our confidence in the estimate of effect. . historical clues and physical findings to recognize all major forms of . TLOC, including mimics, as well as syndromes of orthostatic . . intolerance. . 9.1.4 Model of a syncope unit . The syncope unit should provide minimum core treatments for . . reflex syncope and OH, and treatments or preferential access for 9.1.3 Goal of a syncope unit . cardiac syncope, falls, psychogenic syncope, and epilepsy (Table 12). . Although the benefit of a syncope unit or a syncope specialist in the . The tests and assessments available in the syncope unit are detailed different healthcare systems has not been exposed to rigorous . in Table 13.
Table 12 Structure of the syncope unit
Staffing of a syncope unit is composed of: (1) One or more physicians of any specialty who are syncope specialists. Owing to the multidisciplinary nature of TLOC management, each syn- cope unit should identify specific specialists for the syncope unit and for consultancies. (2) A staff comprising professionals who will advance the care of patients with syncope. These may be physicians, specialized nurses, or others who bring multidisciplinary skills to the facility, coupled with administrative support. The roles played by members of the team may vary according to local circumstances and individual skill. Nurses may be expected to take very important roles including initial assessment, follow-up clinic evalua- tion, selection of investigations (including tilt testing), and implantation/insertion of ECG loop recorders according to predefined protocols and local regulations (see Table 14). (3) Given that the syncope unit is integrated within a hospital organization, syncope specialists and staff are not necessarily employed full-time, but frequently have other duties depending on the volume of activity in the unit.
Facility, protocol, and equipment (1) A syncope unit will deliver most of its care to outpatients in addition to ED and inpatients. (2) The syncope unit should follow an internal protocol, which applies to diagnosis and management and is agreed by stakeholders. (3) An equipped facility must be available. (4) Essential equipment/tests: - 12-lead ECG and 3-lead ECG monitoring - Non-invasive beat-to-beat BP monitor with recording facilities for subsequent analysis - Tilt-table - Holter monitors/external loop recorders - ILRs - Follow-up of ILRsa - 24-hour BP monitoring - Basic autonomic function tests. (5) Established procedures for: - Echocardiography - EPS - Stress test - Neuroimaging tests. (6) Specialists’ consultancies (cardiology, neurology, internal medicine, geriatric, psychology), when needed.
Therapy Patients with syncope will receive their therapy under the care of the syncope unit unless expertise outside that of the unit is required. Database management The syncope unit is required to keep medical records that should also include follow-up when appropriate. The database will also offer the possibil- ity of collaborative research with other syncope units. BP = blood pressure; ECG = electrocardiogram; ED = emergency department; EPS = electrophysiological study; ILR = implantable loop recorder; TLOC = transient loss of consciousness.
aImplantation of loop recorders may be performed either by syncope unit physicians or by external cardiologists at the request of the syncope unit physicians.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 53
Table 13 Test and assessments available in a syncope unit
Initial assessment
History and physical evaluation including 3-min orthostatic BP measurementa 12-lead standard ECG Subsequent tests and assessments (only when indicated)
Blood tests Electrolytes, haemoglobin, troponin, B-type natriuretic peptide, glucose, D-dimer, haemogas anal- ysis/oxygen saturation
Provocative tests CSM, tilt testing
Monitoring External loop recording, implantable loop recording, ambulatory 1–7 days ECG monitoring, 24–48-hour BP monitoring
Autonomic function tests Standing test, Valsalva manoeuvre, deep-breathing test, cold pressor test, and/or established pro- cedures for access to other autonomic function tests
Cardiac evaluation Established procedures for access to echocardiogram, stress test, electrophysiological study, cor- onary angiography
Neurological evaluation Established procedures for access to neurological tests (computed tomography, magnetic reso- nance imaging, EEG, video-EEG)
Geriatric evaluation Established procedures for access to fall risk assessment (cognitive, gait and balance, visual, envi- ronmental) and for gait and balance retraining
Psychological or psychiatric evaluation Established procedures for access to psychological or psychiatric consultancy (mental health problem or psychogenic syncope)
BP = blood pressure; CSM = carotid sinus massage; ECG = electrocardiogram; EEG = electroencephalogram. aPostural orthostatic tachycardia may require longer period of standing.
. 9.1.5 Access and referrals to a syncope unit . 9.2 The clinical nurse specialist in the . Referral can be direct from family practitioners, EDs, in-hospital and . syncope unit out-hospital services, or self-referral from the patient. Fast-track . . 9.2.1 Definition access with a separate waiting list and scheduled follow-up visits is . . The syncope unit clinical nurse specialist is defined as an experienced recommended. In particular, patients at low/intermediate risk admit- . . practitioner who has sufficient knowledge of history features and ted to the ED should benefit from such fast-track facilities (so-called . . physical findings to recognize all major forms of TLOC, as well as syn- protected discharge or advanced access with an appointment for . . dromes of orthostatic intolerance. The clinical nurse specialist should early assessment) to reduce hospitalization rates, directly from the . . work in close collaboration with the syncope specialist. The core ED or after a short stay in the short observation unit of the ED (see . . competencies of the clinical nurse specialist include a specialized clini- section 4.1.2). . . cal focus, patient advocacy, education and training, auditing, research, . . and inter- and intradisciplinary consultations. . 9.1.6 Outcomes and quality indicators . . 9.2.2 Role and skills of the clinical nurse specialist The EHRA Task Force63 has developed the following preliminary . . The clinical nurse specialist should be skilled in the performance and quality indicators, based on consensus, as a rough guide for . . interpretation of structured history taking, 12-lead ECG and routine practitioners: . . blood test results, tilt testing, active stand tests, autonomic function (1) Absolute rate of undiagnosed TLOC should be reduced by 20%; . tests, ECG monitoring (Holter and/or external loop recorder), . (2) Less than 20% of low-/intermediate-risk TLOC patients should be . ABPM, ILR monitoring, and subsequent triaging of patients and moni- admitted from the ED; . toring responses to therapy. Other skills will depend on the service . (3) The syncope unit should have a 20% reduction in costs relative . model, e.g. pacemaker interrogation. The clinical nurse specialist may to usual practice and improved outcomes (i.e. <5% readmissions . have responsibility for follow-up clinics for cardiovascular risk factor . for syncope and <20% of paced patients with recurrence at . management, autonomic function testing and monitoring, manage- 1 year). . ment (including education in PCM) of VVS and OH, and follow-up
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 54 ESC Guidelines
Table 14 The role of physicians and staff in performing procedures and tests
Procedure or test Syncope unit Syncope Non-syncope physician unit staff unit personnel
History taking X
Structured history taking (e.g. application of software technologies and algorithms) X
12-lead ECG X
Blood tests X
Echocardiogram and imaging X
CSM X
Active standing test X
Tilt testing (X)a X
Basic autonomic function test X
ECG monitoring (Holter, external loop recorder): administration and interpretation X X
ILR X (X)b
Remote monitoring X
Other cardiac tests (stress test, EPS, angiograms) X
Neurological tests (computed tomography, magnetic resonance imaging, EEG, video-EEG) X
Pacemaker and ICD implantation, catheter ablation X
Patient education, biofeedback training,c and instruction sheet on PCM X X
Final report and clinic note X
Communication with patients, referring physicians, and stakeholders. X X
Follow-up XX
BP = blood pressure; CSM = carotid sinus massage; ECG = electrocardiogram; EEG = electroencephalogram; EPS = electrophysiological study; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; PCM = physical counter-pressure manoeuvres. aPhysician need not be in the room, but a physician adequately trained in resuscitation needs to be in the vicinity of the test. bCurrent practice limited to a few countries. cBiofeedback means that the PCM training session consists of biofeedback training using a continuous BP monitor. Each manoeuvre is demonstrated and explained. The manoeu- vres are practised under supervision, with immediate feedback of the recordings to gain optimal performance.
. of external and internal loop and Holter monitors and ABPM63 . 10. Key messages . (Table 14). . The clinical nurse specialist should be key in developing and deliv- . The ESC Task Force has selected 19 simple rules to guide the diagno- . sis and management of syncope patients with TLOC according to the ering communication strategies and processes for the syncope unit . for all stakeholders—patients and practitioners—and play a pivotal . 2018 ESC Guidelines on syncope: . role in education and training together with the syncope specialist. . Diagnosis: initial evaluation The clinical nurse specialist should be involved in regular auditing and . . (1) At the initial evaluation answer the following four key questions: collection of data to inform quality indicators. See the video in Web . . Was the event TLOC? Practical Instructions section 11. . . In cases of TLOC, are they of syncopal or non-syncopal origin? . In cases of suspected syncope, is there a clear aetiological diagnosis? Although the skill mix of a clinical nurse specialist has not been . . Is there evidence to suggest a high risk of cardiovascular events or exposed to rigorous scientific or economic scrutiny, the consen- . . death? sus is that the clinical nurse specialist should have the neces- . . (2) At the evaluation of TLOC in the ED, answer the following three sary skills to deliver assessment and treatment for syncope and . . key questions: TLOC. Further research is required to establish the benefits. . . Is there a serious underlying cause that can be identified?
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 55
. If the cause is uncertain, what is the risk of a serious outcome? . 16. In patients with OH, select one or more of the following additional . Should the patient be admitted to hospital? . specific treatments according to clinical severity: (3) In all patients, perform a complete history taking, physical examina- . Education regarding lifestyle manoeuvres. . tion (including standing BP measurement), and standard ECG. . Adequate hydration and salt intake. (4) Perform immediate ECG monitoring (in bed or telemetry) in high- . Discontinuation/reduction of hypotensive therapy. . risk patients when there is a suspicion of arrhythmic syncope. . Counter-pressure manoeuvres. (5) Perform an echocardiogram when there is previous known heart . Abdominal binders and/or support stockings. . disease, or data suggestive of structural heart disease or syncope . Head-up tilt sleeping. secondary to cardiovascular cause. . Midodrine or fludrocortisone. . (6) Perform CSM in patients >40 years of age with syncope of unknown . 17. Ensure that all patients with cardiac syncope receive the specific ther- origin compatible with a reflex mechanism. . apy of the culprit arrhythmia and/or of the underlying disease. . (7) Perform tilt testing in cases where there is suspicion of syncope due . 18. Balance the benefits and harm of ICD implantation in patients with to reflex or an orthostatic cause. . unexplained syncope at high risk of SCD (e.g. those affected by left . (8) Perform blood tests when clinically indicated, e.g. haematocrit and . ventricle systolic dysfunction, HCM, ARVC, or inheritable arrhyth- cell blood count when haemorrhage is suspected, oxygen saturation . mogenic disorders). In this situation, unexplained syncope is defined as . and blood gas analysis when hypoxic syndromes are suspected, tro- . syncope that does not meet any class I diagnostic criterion defined in ponin when cardiac ischaemia-related syncope is suspected, and D- . the tables of recommendations of the 2018 ESC Guidelines on syn- . dimer when pulmonary embolism is suspected, etc. . cope and is considered a suspected arrhythmic syncope. . 19. Re-evaluate the diagnostic process and consider alternative therapies Diagnosis: subsequent investigations . . if the above rules fail or are not applicable to an individual patient. . 9. Perform prolonged ECG monitoring (external or implantable) in . Bear in mind that Guidelines are only advisory. Even though they are . based on the best available scientific evidence, treatment should be patients with recurrent severe unexplained syncope who have all of . . tailored to an individual patient’s need. the following three features: . Clinical or ECG features suggesting arrhythmic syncope. . . A high probability of recurrence of syncope in a reasonable time. . 11. Gaps in evidence and areas for Who may benefit from a specific therapy if a cause for syncope is . . found. . future research 10. Perform EPS in patients with unexplained syncope and bifascicular . . Clinicians responsible for managing patients with TLOC must fre- BBB (impending high-degree AV block) or suspected tachycardia. . . quently make treatment decisions without adequate evidence or a 11. Perform an exercise stress test in patients who experience syncope . . consensus of expert opinion. The following is a short list of selected, during or shortly after exertion. . . common issues that deserve to be addressed in future clinical 12. Consider basic autonomic function tests (Valsalva manoeuvre and . . research. deep-breathing test) and ABPM for the assessment of autonomic . . function in patients with suspected neurogenic OH. . . 13. Consider video recording (at home or in hospital) of TLOC sus- . Diagnosis: the gap between the best pected to be of non-syncopal nature. . available scientific evidence and the need . . for the dissemination of these concepts Treatment . . into clinical practice 14. To all patients with reflex syncope and OH, explain the diagnosis, . . There is wide variation in the practice of syncope evaluation, and reassure, explain the risk of recurrence, and give advice on how to . . wide variation in the adoption of recommendations from pub- avoid triggers and situations. These measures are the cornerstone of . . lished guidelines. The absence of a systematic approach to TLOC treatment and have a high impact in reducing the recurrence of . . incurs higher health and social care costs, unnecessary hospitaliza- syncope. . . tions and diagnostic procedures, prolongation of hospital stays, 15. In patients with severe forms of reflex syncope, select one or more of . . lower diagnostic rates, and higher rates of misdiagnoses and symp- the following additional specific treatments according to the clinical . . tom recurrence. features: . . Therefore, there is a need for: Midodrine or fludrocortisone in young patients with low BP . phenotype. . 1) Large clinical studies that assess the diagnostic yield and compliance of a . Counter-pressure manoeuvres (including tilt training if needed) in . guideline-based standardized systematic approach young patients with prodromes. . . ILR-guided management strategy in selected patients without . Despite the recommendation from the ESC Guidelines on syncope, or with short prodromes. . syncope units are not widely established in clinical practice. Barriers to . Discontinuation/reduction of hypotensive therapy targeting a . establishing a syncope unit include lack of resources, lack of trained systolic BP of 140 mmHg in old hypertensive patients. . dedicated staff, and complex presentations to multiple settings, necessi- . Pacemaker implantation in old patients with dominant . tating involvement from multiple disciplines. The evidence for the use- cardioinhibitory forms. . fulness of syncope units is controversial.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 56 ESC Guidelines
Therefore, there is a need for: . Therefore, there is strong urgent need for RCTs on the efficacy of: . . 2) Large clinical studies that test the superiority of management in a dedicated . 4) Pharmacological therapies targeted to specific subgroups of reflex syncope. syncope facility vs. conventional management . 5) Pacemaker therapy targeted to specific subgroups of cardioinhibitory reflex . . syncope. . 6) Pharmacological therapies of OH-mediated syncope. Diagnosis: the need for new diagnostic . tests and devices . 7) ICD therapy targeted to specific subgroups of patients with unexplained syn- . cope at risk of SCD. BP recording is crucial for the majority of clinical TLOC situations . . and will yield important information for the treatment of syncope. . Unfortunately, current long-term BP (or surrogate) recording sys- . . tems are not optimal for diagnostic use in the syncope evaluation . Treatment: the need for new therapies setting. . . There is a need to move towards personalized medicine. Improving Therefore, there is a need for: . . our knowledge of the biochemical mechanisms underlying specific . forms of reflex syncope will allow the development of new therapies 3) Development and validation of new diagnostic multiparametric devices that . can record heart rhythm and BP (and possibly other physiological parameters . in such specific settings. For example, a low adenosine phenotype . and a low norepinephrine phenotype have been recently identified. such as cerebral saturation or EEG) at the time of a syncopal event. . . Therefore, there is a need for: . Treatment: lack of evidence of efficacy of . 8) Randomized clinical trials on the efficacy of theophylline (and other xantine . most available therapies . antagonists) for low adenosine syncope and norepinephrine transport inhibi- . tors for low epinephrine syncope. Only a few small RCTs have been conducted on treatment of syncope. . In addition, syncopal recurrences are unpredictable and often decrease . . Syncope is a transient phenomenon. The ideal therapy should be spontaneously after medical assessment, even in the absence of a specific . . one that is administered only when needed. therapy. The consequence of the spontaneous decrease is that any ther- . . Therefore, there is a need for: apy for syncope prevention appears to be more effective than it actually . is, making the results of observational data on therapy questionable in . 9) Randomized clinical trials of on-demand administration of specific therapy . the absence of a control group. No therapy can be effective for all . based on specific sensors similar to adrenalin injectors in asthma or nasal patients. Any therapy should be assessed in homogeneous subgroups. . spray for paroxysmal SVT.
12. ‘What to do’ and ‘what not to do’ messages from the Guidelines
Recommendations Class Level
Diagnostic criteria with initial evaluation
VVS is highly probable if syncope is precipitated by pain, fear, or standing, and is associated with typical progressive pro- I C drome (pallor, sweating, and/or nausea).8,13–17
Situational reflex syncope is highly probable if syncope occurs during or immediately after specific triggers listed in Table 3.8,13–17 I C
Syncope due to OH is confirmed when syncope occurs while standing and there is concomitant OH.18–24 I C
Arrhythmic syncope is highly probable when the ECG shows25–39: • Persistent sinus bradycardia <40 b.p.m. or sinus pauses >3 s in the awake state and in the absence of physical training. • Mobitz II second- and third-degree AV block. • Alternating left and right BBB. I C • VT or rapid paroxysmal SVT. • Non-sustained episodes of polymorphic VT and long or short QT interval. • Pacemaker or ICD malfunction with cardiac pauses. Continued
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 57
Management of syncope in the ED
It is recommended that patients with low-risk features, likely to have reflex or situational syncope or syncope due to OH, I B are discharged from the ED.27,35,36,49–54,58,62,69
It is recommended that patients with high-risk features receive an early intensive prompt evaluation in a syncope unit or in I B an ED observation unit (if available), or are hospitalized.26,27,35,36,44–46,50,55–57,59,60,70–76
It is recommended that patients who have neither high- nor low-risk features are observed in the ED or in a syncope unit I B instead of being hospitalized.40,63–65,77
CSM
CSM is indicated in patients >40 years of age with syncope of unknown origin compatible with a reflex mechanism.92–94 I B
CSS is confirmed if CSM causes bradycardia (asystole) and/or hypotension that reproduces spontaneous symptoms, and I B patients have clinical features compatible with a reflex mechanism of syncope.89,90,92,93,98–102
Active standing
Intermittent determination by sphygmomanometer of BP and HR while supine and during active standing for 3 min are indi- I C cated at initial syncope evaluation.20,103,104
Syncope due to OH is confirmed when there is a fall in systolic BP from a baseline value >_20 mmHg, diastolic BP >_10 I C mmHg, or a decrease in systolic BP to <90 mmHg that reproduces spontaneous symptoms.6,20,103,104
ECG monitoring
Immediate in-hospital monitoring (in bed or by telemetry) is indicated in high-risk patients (defined in Table 6). I C
ILR is indicated in an early phase of evaluation in patients with recurrent syncope of uncertain origin, absence of high-risk criteria (listed in Table 6), and a high likelihood of recurrence within the battery life of the device.175,176,181–184,202, I A Supplementary Data Table 5
ILR is indicated in high-risk (criteria listed in Table 6) patients in whom a comprehensive evaluation did not demonstrate a cause of syncope or lead to a specific treatment, and who do not have conventional indications for primary prevention ICD I A or pacemaker indication.174,180,187,188,195, Supplementary Data Tables 5 and 6
Arrhythmic syncope is confirmed when a correlation between syncope and an arrhythmia (bradyarrhythmia or tachyar- I B rhythmia) is detected.172,184–186,188,200
EPS
In patients with syncope and previous myocardial infarction or other scar-related conditions, EPS is indicated when syncope I B remains unexplained after non-invasive evaluation.218
In patients with unexplained syncope and bifascicular BBB, a pacemaker is indicated in the presence of either a baseline H-V interval of >_70 ms, second- or third-degree His-Purkinje block during incremental atrial pacing, or with pharmacological I B challenge.188,214–217,221
In patients with unexplained syncope and previous myocardial infarction or other scar-related conditions, it is recom- I B mended that induction of sustained monomorphic VT is managed according to the current ESC Guidelines for VA.46
In patients without structural heart disease with syncope preceded by sudden and brief palpitations, it is recommended that the induction of rapid SVT or VT, which reproduces hypotensive or spontaneous symptoms, is managed with appropriate I C therapy according to the current ESC Guidelines.46,222
Echocardiography
Echocardiography is indicated for diagnosis and risk stratification in patients with suspected structural heart disease.235,236 I B
Exercise testing
Exercise testing is indicated in patients who experience syncope during or shortly after exertion. I C
Syncope due to second- or third-degree AV block is confirmed when the AV block develops during exercise, even without I C syncope.253–257
250–252 Reflex syncope is confirmed when syncope is reproduced immediately after exercise in the presence of severe hypotension. I C Continued
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 58 ESC Guidelines
Treatment of reflex syncope
Explanation of the diagnosis, provision of reassurance, and explanation of the risk of recurrence and the avoidance of trig- I B gers and situations are indicated in all patients. Supplementary Data Table 10
279,280 Beta-adrenergic blocking drugs are not indicated. III A
299,300 Cardiac pacing is not indicated in the absence of a documented cardioinhibitory reflex. III B
Treatment of OH
Explanation of the diagnosis, provision of reassurance, and explanation of the risk of recurrence and the avoidance of trig- I C gers and situations are indicated in all patients.
Adequate hydration and salt intake are indicated.310,311 I C
Treatment of syncope due to cardiac arrhythmias
Cardiac pacing is indicated when there is an established relationship between syncope and symptomatic I B bradycardia.200,210–212,255,334–338,341
Cardiac pacing is indicated in patients with intermittent/paroxysmal intrinsic third- or second-degree AV block (including I C AF with slow ventricular conduction), although there is no documentation of a correlation between symptoms and ECG.
Cardiac pacing is not indicated in patients when there are reversible causes for bradycardia. III C
Cardiac pacing is indicated in patients with syncope, BBB, and a positive EPS or ILR-documented AV block.188,217 I B
Catheter ablation is indicated in patients with syncope due to SVT or VT in order to prevent syncope recurrence. I C
An ICD is indicated in patients with syncope due to VT and ejection fraction <_35%.46 I A
218 An ICD is indicated in patients with syncope and previous myocardial infarction who have VT induced during EPS. I C
ICD indications in patients with unexplained syncope and left ventricular systolic dysfunction
ICD therapy is recommended to reduce SCD in patients with symptomatic heart failure (NYHA class II–III) and LVEF <_35% after >_3 months of optimal medical therapy, who are expected to survive for >_1 year with good functional status.46 I A systolic dysfunction
Syncope in patients with comorbidity and frailty
A multifactorial evaluation and intervention is recommended in older patients because more than one possible cause for I B syncope and unexplained fall may be present.33,372–374,376–380
Neurological evaluation
Neurological evaluation is indicated when syncope is suspected to be epilepsy or due to autonomic failure to evaluate the I C underlying disease.
AF = atrial fibrillation; AV = atrioventricular; BBB = bundle branch block; BP = blood pressure; b.p.m. = beats per minute; CSM = carotid sinus massage; CSS = carotid sinus syn- drome; ECG = electrocardiogram; ED = emergency department; EPS = electrophysiological study; ESC = European Society of Cardiology; HR = heart rate; ICD = implantable cardioverter defibrillator; ILR = implantable loop recorder; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; OH = orthostatic hypotension; SCD = sudden cardiac death; SVT = supraventricular tachycardia; VA = ventricular arrhythmia; VT = ventricular tachycardia; VVS = vasovagal syncope.
. 13. Supplementary Data and Web . 14. Appendix . Practical Instructions . . ESC Committee for Practice Guidelines (CPG): Stephan . Windecker (Chairperson) (Switzerland), Victor Aboyans (France), Supplementary Data with additional Web Tables complementing the . . Stefan Agewall (Norway), Emanuele Barbato (Italy), He´ctor Bueno full text, and an additional Web Practical Instructions document— . . (Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan with a glossary containing definitions of syncope and related concepts . . Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado with tracings, videos, flow charts, and checklists—are available on the . . (The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli European Heart Journal website and via the ESC Website at www. . . (Switzerland), Gerhard Hindricks (Germany), Bernard Iung escardio.org/guidelines. . . (France), Peter Ju¨ni (Canada), Hugo Albert Katus (Germany), Juhani
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 59
. Knuuti (Finland), Patrizio Lancellotti (Belgium), Christophe . 3. Alboni P, Alboni M. Vasovagal syncope. Heidelberg: Springer; 2015. p3–17. . 4. Deharo JC, Guieu R, Mechulan A, Peyrouse E, Kipson N, Ruf J, Gerolami V, Leclercq (France), Theresa McDonagh (UK), Massimo Francesco . . Devoto G, Marre V, Brignole M. Syncope without prodromes in patients with Piepoli (Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), . normal heart and normal electrocardiogram: a distinct entity. J Am Coll Cardiol . 2013;62:1075–1080. Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Miguel Sousa- . Uva (Portugal), Iain A. Simpson (UK), Jose Luis Zamorano (Spain). . 5. Brignole M, Deharo JC, De Roy L, Menozzi C, Blommaert D, Dabiri L, Ruf J, . Guieu R. Syncope due to idiopathic paroxysmal atrioventricular block: long- ESC National Cardiac Societies actively involved in the review . term follow-up of a distinct form of atrioventricular block. J Am Coll Cardiol . 2011;58:167–173. process of the 2018 ESC Guidelines for the diagnosis and . 6. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, management of syncope: . Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth . R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, . Austria: Austrian Society of Cardiology, Franz Xaver Roithinger; . Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, Belarus: Belorussian Scientific Society of Cardiologists, Alexandr . van Dijk JG. Consensus statement on the definition of orthostatic hypotension, . neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Chasnoits; Belgium: Belgian Society of Cardiology, Yves . Res 2011;21:69–72. . Vandekerckhove; Bulgaria: Bulgarian Society of Cardiology, Vasil B. . 7. Fedorowski A, Melander O. Syndromes of orthostatic intolerance: a hidden Traykov; Croatia: Croatian Cardiac Society, Davor Puljevic; . danger. J Intern Med 2013;273:322–335. . 8. Wieling W, Thijs RD, van Dijk N, Wilde AA, Benditt DG, van Dijk JG. Cyprus: Cyprus Society of Cardiology, Elias Papasavvas; Czech . Symptoms and signs of syncope: a review of the link between physiology and . Republic: Czech Society of Cardiology, Josef Kautzner; Denmark: . clinical clues. Brain 2009;132:2630–2642. Danish Society of Cardiology, Henning Mølgaard; Egypt: Egyptian . 9. van Dijk JG, Thijs RD, van Zwet E, Tannemaat MR, van Niekerk J, Benditt DG, . Wieling W. The semiology of tilt-induced reflex syncope in relation to electro- Society of Cardiology, Mostafa Nawar; Finland: Finnish Cardiac . encephalographic changes. Brain 2014;137:576–585. Society, Hannu Parikka; The Former Yugoslav Republic of . 10. Breningstall GN. Breath-holding spells. Pediatr Neurol 1996;14:91–97. . 11. Stephenson JBP. Fits and faints. London: Mac Keith Press; 1990, 202 pages. Macedonia: Macedonian FYR Society of Cardiology, Marija Vavlukis; . . 12. van Dijk N, Boer KR, Colman N, Bakker A, Stam J, van Grieken JJ, Wilde AA, France: French Society of Cardiology, Olivier Piot; Georgia: . . Linzer M, Reitsma JB, Wieling W. High diagnostic yield and accuracy of history, Georgian Society of Cardiology, Kakhaber Etsadashvili; Germany: . physical examination, and ECG in patients with transient loss of consciousness in . FAST: the Fainting Assessment study. J Cardiovasc Electrophysiol 2008;19:48–55. German Cardiac Society, Thomas Klingenheben; Greece: Hellenic . . 13. Stephenson J. Chapter 7 - Anoxic seizures or syncope. Fits and faints. Oxford: Society of Cardiology, Spyridon Deftereos; Hungary: Hungarian . Blackwell Scientific Publications; 1990. p41–57. Society of Cardiology, L aszloS aghy; Iceland: Icelandic Society of . 14. van Dijk JG, Sheldon R. Is there any point to vasovagal syncope? Clin Auton Res . 2008;18:167–169. Cardiology, Kristjan Gudmundsson; Israel: Israel Heart Society, Roy . . 15. Alboni P, Alboni M, Bertorelle G. The origin of vasovagal syncope: to protect Beinart; Italy: Italian Federation of Cardiology, Antonio Raviele; . the heart or to escape predation? Clin Auton Res 2008;18:170–178. Kazakhstan: Association of Cardiologists of Kazakhstan, Ayan . 16. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and . triggers of syncope in medical students. Am J Cardiol 2003;91:1006–1008, A8. Abdrakhmanov; Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin . . 17. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical stu- Mirrakhimov, Latvia: Latvian Society of Cardiology, Oskars Kalejs; . dents and their first-degree relatives. Eur Heart J 2006;27:1965–1970. Libya: Libyan Cardiac Society, Hisham A. Benlamin; Lithuania: . 18. Shibao C, Lipsitz LA, Biaggioni I. ASH position paper: evaluation and treatment . of orthostatic hypotension. J Clin Hypertens (Greenwich) 2013;15:147–153. Lithuanian Society of Cardiology, Aras Puodziukynas; Luxembourg: . . 19. Mathias CJ, Mallipeddi R, Bleasdale-Barr K. Symptoms associated with ortho- Luxembourg Society of Cardiology, Carlo Dimmer; Malta: Maltese . static hypotension in pure autonomic failure and multiple system atrophy. Cardiac Society, Mark A. Sammut; Moldova: Moldavian Society of . J Neurol 1999;246:893–898. . 20. Naschitz JE, Rosner I. Orthostatic hypotension: framework of the syndrome. Cardiology, Aurica Raducan; Montenegro: Montenegro Society . . Postgrad Med J 2007;83:568–574. of Cardiology, Mihailo Vukmirovi c; Morocco: Moroccan Society of . 21. Consensus statement on the definition of orthostatic hypotension, pure auto- Cardiology, Salima Abdelali; The Netherlands: Netherlands . nomic failure, and multiple system atrophy. J Neurol Sci 1996;144:218–219. . 22. Wieling W, Krediet CT, van Dijk N, Linzer M, Tschakovsky ME. Initial ortho- Society of Cardiology, Martin E.W. Hemels; Norway: Norwegian . . static hypotension: review of a forgotten condition. Clin Sci (Lond) Society of Cardiology, Kristina H. Haugaa; Poland: Polish Cardiac . 2007;112:157–165. Society, Rafał Baranowski; Portugal: Portuguese Society of . 23. Podoleanu C, Maggi R, Brignole M, Croci F, Incze A, Solano A, Puggioni E, . Carasca E. Lower limb and abdominal compression bandages prevent progres- Cardiology, Pedro Silva Cunha; Romania: Romanian Society of . . sive orthostatic hypotension in elderly persons: a randomized single-blind con- Cardiology, Gheorghe-Andrei Dan; Russian Federation: Russian . trolled study. J Am Coll Cardiol 2006;48:1425–1432. Society of Cardiology, Tatyana Tyurina; San Marino: San Marino . 24. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of . orthostatic intolerance. Neurology 2006;67:28–32. Society of Cardiology, Luca Bertelli; Slovakia: Slovak Society of . 25. Sarasin FP, Hanusa BH, Perneger T, Louis-Simonet M, Rajeswaran A, Kapoor . Cardiology, Peter Mitro; Spain: Spanish Society of Cardiology, . WN. A risk score to predict arrhythmias in patients with unexplained syncope. Ignacio Fern andez Lozano; Sweden: Swedish Society of Cardiology, . Acad Emerg Med 2003;10:1312–1317. . 26. Quinn J, McDermott D, Stiell I, Kohn M, Wells G. Prospective validation of the Lennart Bergfeldt; Switzerland: Swiss Society of Cardiology, Stefan . San Francisco Syncope Rule to predict patients with serious outcomes. Ann . Osswald; Tunisia: Tunisian Society of Cardiology and Cardio- . Emerg Med 2006;47:448–454. Vascular Surgery, Ben Halima Afef; Tu rkey : Turkish Society of . 27. Middlekauff HR, Stevenson WG, Stevenson LW, Saxon LA. Syncope in € . advanced heart failure: high risk of sudden death regardless of origin of syncope. Cardiology, H. Murat Ozdem ır; United Kingdom: British . J Am Coll Cardiol 1993;21:110–116. Cardiovascular Society, P. Boon Lim. . 28. Brembilla-Perrot B, Suty-Selton C, Beurrier D, Houriez P, Nippert M, de la . Chaise AT, Louis P, Claudon O, Andronache M, Abdelaal A, Sadoul N, Juilliere . Y. Differences in mechanisms and outcomes of syncope in patients with coro- 15. References . . nary disease or idiopathic left ventricular dysfunction as assessed by electrophy- 1. Mosqueda-Garcia R, Furlan R, Tank J, Fernandez-Violante R. The elusive patho- . siologic testing. J Am Coll Cardiol 2004;44:594–601. physiology of neurally mediated syncope. Circulation 2000;102:2898–2906. . 29. Steinberg JS, Beckman K, Greene HL, Marinchak R, Klein RC, Greer SG, 2. Morillo CA, Eckberg DL, Ellenbogen KA, Beightol LA, Hoag JB, Tahvanainen . Ehlert F, Foster P, Menchavez E, Raitt M, Wathen MS, Morris M, Hallstrom A. KU, Kuusela TA, Diedrich AM. Vagal and sympathetic mechanisms in patients . Follow-up of patients with unexplained syncope and inducible ventricular with orthostatic vasovagal syncope. Circulation 1997;96:2509–2513. . tachyarrhythmias: analysis of the AVID registry and an AVID substudy.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 60 ESC Guidelines
. Antiarrhythmics Versus Implantable Defibrillators. J Cardiovasc Electrophysiol . orthostatic hypotension: a meta-analysis of prospective observational studies. 2001;12:996–1001. . Eur Heart J 2015;36:1609–1617. . 30. Pezawas T, Stix G, Kastner J, Wolzt M, Mayer C, Moertl D, Schmidinger H. . 49.CalkinsH,ShyrY,FruminH,SchorkA,MoradyF.Thevalueofthe Unexplained syncope in patients with structural heart disease and no docu- . clinical history in the differentiation of syncope due to ventricular mented ventricular arrhythmias: value of electrophysiologically guided implant- . tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med . able cardioverter defibrillator therapy. Europace 2003;5:305–312. . 1995;98:365–373. 31. Olshansky B, Poole JE, Johnson G, Anderson J, Hellkamp AS, Packer D, Mark . 50. Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML, Frenneaux M. DB, Lee KL, Bardy GH, SCD-HeFT Investigators. Syncope predicts the out- . Diagnostic criteria for vasovagal syncope based on a quantitative history. Eur come of cardiomyopathy patients: analysis of the SCD-HeFT study. J Am Coll . Heart J 2006;27:344–350. Cardiol 2008;51:1277–1282. . 51. Lipsitz LA. Syncope in the elderly patient. Hosp Pract (Off Ed) 1986;21:33–44. 32. Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, Maron . 52. Dermksian G, Lamb LE. Syncope in a population of healthy young adults; inci- BJ, Page RL, Passman RS, Siscovick D, Siscovick D, Stevenson WG, Zipes DP, . dence, mechanisms, and significance. J Am Med Assoc 1958;168:1200–1207. . American Heart Association, American College of Cardiology Foundation, . 53. Brignole M, Oddone D, Cogorno S, Menozzi C, Gianfranchi L, Bertulla A. Long- Heart Rhythm Society. American Heart Association/American College of . term outcome in symptomatic carotid sinus hypersensitivity. Am Heart J Cardiology Foundation/Heart Rhythm Society scientific statement on noninva- . 1992;123:687–692. sive risk stratification techniques for identifying patients at risk for sudden car- . 54. Jamjoom AA, Nikkar-Esfahani A, Fitzgerald JE. Operating theatre related . diac death: a scientific statement from the American Heart Association Council . syncope in medical students: a cross sectional study. BMC Med Educ 2009;9:14. on Clinical Cardiology Committee on Electrocardiography and Arrhythmias . 55. Quinn JV, Stiell IG, McDermott DA, Sellers KL, Kohn MA, Wells GA. and Council on Epidemiology and Prevention. Circulation 2008;118:1497–1518. . Derivation of the San Francisco Syncope Rule to predict patients with short- 33. Del Rosso A, Alboni P, Brignole M, Menozzi C, Raviele A. Relation of clinical . term serious outcomes. Ann Emerg Med 2004;43:224–232. . presentation of syncope to the age of patients. Am J Cardiol . 56. Costantino G, Perego F, Dipaola F, Borella M, Galli A, Cantoni G, Dell’Orto S, 2005;96:1431–1435. . Dassi S, Filardo N, Duca PG, Montano N, Furlan R, STePS Investigators. Short- 34. Martin TP, Hanusa BH, Kapoor WN. Risk stratification of patients with syncope. . and long-term prognosis of syncope, risk factors, and role of hospital admission: . Ann Emerg Med 1997;29:459–466. . results from the STePS (Short-Term Prognosis of Syncope) study. J Am Coll 35. Colivicchi F, Ammirati F, Melina D, Guido V, Imperoli G, Santini M, OESIL . Cardiol 2008;51:276–283. (Osservatorio Epidemiologico sulla Sincope nel Lazio) Study Investigators. . 57. Colman N, Bakker A, Linzer M, Reitsma JB, Wieling W, Wilde AA. Value of Development and prospective validation of a risk stratification system for . history-taking in syncope patients: in whom to suspect long QT syndrome? patients with syncope in the emergency department: the OESIL risk score. Eur . Europace 2009;11:937–943. Heart J 2003;24:811–819. . 58. Kapoor WN, Peterson J, Wieand HS, Karpf M. Diagnostic and prognostic impli- 36. Del Rosso A, Ungar A, Maggi R, Giada F, Petix NR, De Santo T, Menozzi C, . cations of recurrences in patients with syncope. Am J Med 1987;83:700–708. . Brignole M. Clinical predictors of cardiac syncope at initial evaluation in patients . 59. Oh JH, Hanusa BH, Kapoor WN. Do symptoms predict cardiac arrhythmias referred urgently to a general hospital: the EGSYS score. Heart . and mortality in patients with syncope? Arch Intern Med 1999;159:375–380. 2008;94:1620–1626. . 60. Grossman SA, Fischer C, Lipsitz LA, Mottley L, Sands K, Thompson S, 37. Mittal S, Hao SC, Iwai S, Stein KM, Markowitz SM, Slotwiner DJ, Lerman BB. . Zimetbaum P, Shapiro NI. Predicting adverse outcomes in syncope. J Emerg . Significance of inducible ventricular fibrillation in patients with coronary artery . Med 2007;33:233–239. disease and unexplained syncope. J Am Coll Cardiol 2001;38:371–376. . 61. Surawicz B, Childers R, Deal BJ, Gettes LS, Bailey JJ, Gorgels A, Hancock EW, 38. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M, Solano A, . Josephson M, Kligfield P, Kors JA, Macfarlane P, Mason JW, Mirvis DM, Okin P, Bottoni N. Diagnostic value of history in patients with syncope with or without . Pahlm O, Rautaharju PM, van Herpen G, Wagner GS, Wellens H, American . heart disease. J Am Coll Cardiol 2001;37:1921–1928. . Heart Association Electrocardiography and Arrhythmias Committee, Council 39. Berecki-Gisolf J, Sheldon A, Wieling W, van Dijk N, Costantino G, Furlan R, . on Clinical Cardiology, American College of Cardiology Foundation, Heart Shen WK, Sheldon R. Identifying cardiac syncope based on clinical history: a . Rhythm Society. AHA/ACCF/HRS recommendations for the standardization . literature-based model tested in four independent datasets. PLoS One . and interpretation of the electrocardiogram: part III: intraventricular conduction 2013;8:e75255. . disturbances: a scientific statement from the American Heart Association 40. Casagranda I, Brignole M, Cencetti S, Cervellin G, Costantino G, Furlan R, . Electrocardiography and Arrhythmias Committee, Council on Clinical . Cardiology; the American College of Cardiology Foundation; and the Heart Mossini G, Numeroso F, Pesenti Campagnoni M, Pinna Parpaglia P, Rafanelli M, . Ungar A. Management of transient loss of consciousness of suspected syncopal . Rhythm Society. Endorsed by the International Society for Computerized cause, after the initial evaluation in the Emergency Department. Emergency Care . Electrocardiology. J Am Coll Cardiol 2009;53:976–981. J 2016;12:25–27. . 62. Costantino G, Sun BC, Barbic F, Bossi I, Casazza G, Dipaola F, McDermott D, . Quinn J, Reed MJ, Sheldon RS, Solbiati M, Thiruganasambandamoorthy V, 41. Crane SD. Risk stratification of patients with syncope in an accident and emer- . gency department. Emerg Med J 2002;19:23–27. . Beach D, Bodemer N, Brignole M, Casagranda I, Del Rosso A, Duca P, 42. Sheldon R, Rose S, Ritchie D, Connolly SJ, Koshman ML, Lee MA, Frenneaux M, . Falavigna G, Grossman SA, Ippoliti R, Krahn AD, Montano N, Morillo CA, . Olshansky B, Raj SR, Ruwald MH, Sarasin FP, Shen WK, Stiell I, Ungar A, Gert Fisher M, Murphy W. Historical criteria that distinguish syncope from seizures. . J Am Coll Cardiol 2002;40:142–148. . van Dijk J, van Dijk N, Wieling W, Furlan R. Syncope clinical management in 43. Numeroso F, Mossini G, Giovanelli M, Lippi G, Cervellin G. Short-term progno- . the emergency department: a consensus from the first international work- sis and current management of syncopal patients at intermediate risk: results . shop on syncope risk stratification in the emergency department. Eur Heart J . 2016;37:1493–1498. from the IRiS (Intermediate-Risk Syncope) study. Acad Emerg Med . 2016;23:941–948. . 63. Kenny RA, Brignole M, Dan GA, Deharo JC, van Dijk JG, Doherty C, Hamdan 44. Reed MJ, Newby DE, Coull AJ, Prescott RJ, Jacques KG, Gray AJ. The ROSE . M, Moya A, Parry SW, Sutton R, Ungar A, Wieling W. Syncope Unit: rationale . and requirement–the European Heart Rhythm Association position statement (Risk Stratification Of Syncope in the Emergency department) study. J Am Coll . Cardiol 2010;55:713–721. . endorsed by the Heart Rhythm Society. Europace 2015;17:1325–1340. 45. Martin GJ, Adams SL, Martin HG, Mathews J, Zull D, Scanlon PJ. Prospective . 64. Sun BC, McCreath H, Liang LJ, Bohan S, Baugh C, Ragsdale L, Henderson SO, evaluation of syncope. Ann Emerg Med 1984;13:499–504. . Clark C, Bastani A, Keeler E, An R, Mangione CM. Randomized clinical trial of . an emergency department observation syncope protocol versus routine inpa- 46. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, . Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck . tient admission. Ann Emerg Med 2014;64:167–175. KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van . 65. Shen WK, Decker WW, Smars PA, Goyal DG, Walker AE, Hodge DO, Trusty . JM, Brekke KM, Jahangir A, Brady PA, Munger TM, Gersh BJ, Hammill SC, Frye Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ven- . . RL. Syncope Evaluation in the Emergency Department Study (SEEDS): a multi- tricular arrhythmias and the prevention of sudden cardiac death: The Task . . disciplinary approach to syncope management. Circulation 2004;110:3636–3645. Force for the Management of Patients with Ventricular Arrhythmias and the . Prevention of Sudden Cardiac Death of the European Society of Cardiology . 66. Thiruganasambandamoorthy V, Stiell IG, Wells GA, Vaidyanathan A, Mukarram . M, Taljaard M. Outcomes in presyncope patients: a prospective cohort study. (ESC). Endorsed by: Association for European Paediatric and Congenital . . Ann Emerg Med 2015;65:268–276.e6. Cardiology (AEPC). Eur Heart J 2015;36:2793–2867. . . 67. Greve Y, Geier F, Popp S, Bertsch T, Singler K, Meier F, Smolarsky A, Mang H, 47. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin EJ, Levy D. . Incidence and prognosis of syncope. N Engl J Med 2002;347:878–885. . Muller C, Christ M. The prevalence and prognostic significance of near syncope 48. Ricci F, Fedorowski A, Radico F, Romanello M, Tatasciore A, Di Nicola M, . and syncope: a prospective study of 395 cases in an emergency department . (the SPEED study). Dtsch Arztebl Int 2014;111:197–204. Zimarino M, De Caterina R. Cardiovascular morbidity and mortality related to .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 61
. 68. Krahn AD, Klein GJ, Yee R, Skanes AC, REVEAL Investigators. Predictive value . Canadian Syncope Risk Score to predict serious adverse events after emer- of presyncope in patients monitored for assessment of syncope. Am Heart J . gency department assessment of syncope. CMAJ 2016;188:E289–E298. . 2001;141:817–821. . 89. Kerr SR, Pearce MS, Brayne C, Davis RJ, Kenny RA. Carotid sinus hypersensitiv- 69. Huff JS, Decker WW, Quinn JV, Perron AD, Napoli AM, Peeters S, Jagoda AS, . ity in asymptomatic older persons: implications for diagnosis of syncope and American College of Emergency Physicians. Clinical policy: critical issues in the . falls. Arch Intern Med 2006;166:515–520. . evaluation and management of adult patients presenting to the emergency . 90. Puggioni E, Guiducci V, Brignole M, Menozzi C, Oddone D, Donateo P, Croci F, department with syncope. Ann Emerg Med 2007;49:431–444. . Solano A, Lolli G, Tomasi C, Bottoni N. Results and complications of the caro- 70. Thiruganasambandamoorthy V, Hess EP, Alreesi A, Perry JJ, Wells GA, Stiell IG. . tid sinus massage performed according to the “method of symptoms”. Am J External validation of the San Francisco Syncope Rule in the Canadian setting. . Cardiol 2002;89:599–601. Ann Emerg Med 2010;55:464–472. . 91. Wieling W, Krediet CT, Solari D, de Lange FJ, van Dijk N, Thijs RD, van Dijk 71. Brignole M, Menozzi C, Bartoletti A, Giada F, Lagi A, Ungar A, Ponassi I, Mussi . JG, Brignole M, Jardine DL. At the heart of the arterial baroreflex: a physiologi- C, Maggi R, Re G, Furlan R, Rovelli G, Ponzi P, Scivales A. A new management . cal basis for a new classification of carotid sinus hypersensitivity. J Intern Med . of syncope: prospective systematic guideline-based evaluation of patients . 2013;273:345–358. referred urgently to general hospitals. Eur Heart J 2006;27:76–82. . 92. Solari D, Maggi R, Oddone D, Solano A, Croci F, Donateo P, Brignole M. 72. Del Greco M, Cozzio S, Scillieri M, Caprari F, Scivales A, Disertori M. . Clinical context and outcome of carotid sinus syndrome diagnosed by means of Diagnostic pathway of syncope and analysis of the impact of guidelines in a dis- . the ‘method of symptoms’. Europace 2014;16:928–934. . trict general hospital. The ECSIT study (epidemiology and costs of syncope in . 93. Solari D, Maggi R, Oddone D, Solano A, Croci F, Donateo P, Wieling W, Trento). Ital Heart J 2003;4:99–106. . Brignole M. Assessment of the vasodepressor reflex in carotid sinus syndrome. 73. McCarthy F, McMahon CG, Geary U, Plunkett PK, Kenny RA, Cunningham CJ, . Circ Arrhythm Electrophysiol 2014;7:505–510. European Society of Cardiology. Management of syncope in the Emergency . 94. Brignole M, Ungar A, Casagranda I, Gulizia M, Lunati M, Ammirati F, Del Rosso . Department: a single hospital observational case series based on the application of . A, Sasdelli M, Santini M, Maggi R, Vitale E, Morrione A, Francese GM, Vecchi European Society of Cardiology Guidelines. Europace 2009;11:216–224. . MR, Giada F, Syncope Unit Project (SUP) investigators. Prospective multicentre 74. Numeroso F, Mossini G, Spaggiari E, Cervellin G. Syncope in the emergency . systematic guideline-based management of patients referred to the Syncope . department of a large northern Italian hospital: incidence, efficacy of a short- . Units of general hospitals. Europace 2010;12:109–118. stay observation ward and validation of the OESIL risk score. Emerg Med J . 95. Munro NC, McIntosh S, Lawson J, Morley CA, Sutton R, Kenny RA. Incidence 2010;27:653–658. . of complications after carotid sinus massage in older patients with syncope. 75. Lin M, Wolfe RE, Shapiro NI, Novack V, Lior Y, Grossman SA. Observation vs . J Am Geriatr Soc 1994;42:1248–1251. admission in syncope: can we predict short length of stays? Am J Emerg Med . 96. Ungar A, Rivasi G, Rafanelli M, Toffanello G, Mussi C, Ceccofiglio A, McDonagh 2015;33:1684–1686. . R, Drumm B, Marchionni N, Alboni P, Kenny RA. Safety and tolerability of Tilt 76. Grossman AM, Volz KA, Shapiro NI, Salem R, Sanchez LD, Smulowitz P, . Testing and Carotid Sinus Massage in the octogenarians. Age Ageing . Grossman SA. Comparison of 1-day emergency department observation and . 2016;45:242–248. inpatient ward for 1-day admissions in syncope patients. J Emerg Med . 97. Davies AJ, Kenny RA. Frequency of neurologic complications following carotid 2016;50:217–222. . sinus massage. Am J Cardiol 1998;81:1256–1257. 77. Ungar A, Tesi F, Chisciotti VM, Pepe G, Vanni S, Grifoni S, Balzi D, Rafanelli M, . 98. Brignole M, Menozzi C, Lolli G, Bottoni N, Gaggioli G. Long-term outcome of . Marchionni N, Brignole M. Assessment of a structured management pathway . paced and nonpaced patients with severe carotid sinus syndrome. Am J Cardiol for patients referred to the Emergency Department for syncope: results in a . 1992;69:1039–1043. tertiary hospital. Europace 2016;18:457–462. . 99. Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and 78. Serrano LA, Hess EP, Bellolio MF, Murad MH, Montori VM, Erwin PJ, Decker . milder symptoms in patients treated with pacing for induced cardioinhibitory WW. Accuracy and quality of clinical decision rules for syncope in the emer- . carotid sinus syndrome: a randomized study. Europace 2007;9:932–936. gency department: a systematic review and meta-analysis. Ann Emerg Med . 100. Menozzi C, Brignole M, Lolli G, Bottoni N, Oddone D, Gianfranchi L, Gaggioli 2010;56:362–373.e1. . G. Follow-up of asystolic episodes in patients with cardioinhibitory, neurally . 79. Dipaola F, Costantino G, Perego F, Borella M, Galli A, Cantoni G, Barbic F, . mediated syncope and VVI pacemaker. Am J Cardiol 1993;72:1152–1155. Casella F, Duca PG, Furlan R, STePS investigators. San Francisco Syncope Rule, . 101. Maggi R, Menozzi C, Brignole M, Podoleanu C, Iori M, Sutton R, Moya A, Giada Osservatorio Epidemiologico sulla Sincope nel Lazio risk score, and clinical . F, Orazi S, Grovale N. Cardioinhibitory carotid sinus hypersensitivity predicts judgment in the assessment of short-term outcome of syncope. Am J Emerg . an asystolic mechanism of spontaneous neurally mediated syncope. Europace . Med 2010;28:432–439. . 2007;9:563–567. 80. Sheldon RS, Morillo CA, Krahn AD, O’Neill B, Thiruganasambandamoorthy V, . 102. Thomas JE. Hyperactive carotid sinus reflex and carotid sinus syncope. Mayo Parkash R, Talajic M, Tu JV, Seifer C, Johnstone D, Leather R. Standardized . Clin Proc 1969;44:127–139. approaches to the investigation of syncope: Canadian Cardiovascular Society . 103. Smit AA, Halliwill JR, Low PA, Wieling W. Pathophysiological basis of ortho- . position paper. Can J Cardiol 2011;27:246–253. . static hypotension in autonomic failure. J Physiol 1999;519:1–10. 81. Perego F, Costantino G, Dipaola F, Scannella E, Borella M, Galli A, Barbic F, . 104. Ricci F, De Caterina R, Fedorowski A. Orthostatic hypotension: epidemiology, Casella F, Solbiati M, Angaroni L, Duca P, Furlan R. Predictors of hospital admis- . prognosis, and treatment. J Am Coll Cardiol 2015;66:848–860. . sion after syncope: relationships with clinical risk scores. Int J Cardiol . 105. Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigat- 2012;161:182–183. . ing unexplained syncope. Lancet 1986;1:1352–1355. 82. Schladenhaufen R, Feilinger S, Pollack M, Benenson R, Kusmiesz AL. Application . 106. Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo G, of San Francisco Syncope Rule in elderly ED patients. Am J Emerg Med . Menozzi C, Raviele A, Sutton R. ‘The Italian Protocol‘: a simplified head-up tilt 2008;26:773–778. . testing potentiated with oral nitroglycerin to assess patients with unexplained 83. Sun BC, Mangione CM, Merchant G, Weiss T, Shlamovitz GZ, Zargaraff G, . syncope. Europace 2000;2:339–342. Shiraga S, Hoffman JR, Mower WR. External validation of the San Francisco . 107. Kenny RA, O’Shea D, Parry SW. The Newcastle protocols for head-up tilt table . Syncope Rule. Ann Emerg Med 2007;49:420–427, 427.e1–4. . testing in the diagnosis of vasovagal syncope, carotid sinus hypersensitivity, and 84. Reed MJ, Henderson SS, Newby DE, Gray AJ. One-year prognosis after syn- . related disorders. Heart 2000;83:564–569. cope and the failure of the ROSE decision instrument to predict one-year . 108. Benditt DG, Ferguson DW, Grubb BP, Kapoor WN, Kugler J, Lerman BB, Maloney adverse events. Ann Emerg Med 2011;58:250–256. . JD, Raviele A, Ross B, Sutton R, Wolk MJ, Wood DL. Tilt table testing for assessing . 85. Birnbaum A, Esses D, Bijur P, Wollowitz A, Gallagher EJ. Failure to validate the . syncope. American College of Cardiology. J Am Coll Cardiol 1996;28:263–275. San Francisco Syncope Rule in an independent emergency department popula- . 109. Morillo CA, Klein GJ, Zandri S, Yee R. Diagnostic accuracy of a low-dose iso- tion. Ann Emerg Med 2008;52:151–159. . proterenol head-up tilt protocol. Am Heart J 1995;129:901–906. 86. Costantino G, Casazza G, Reed M, Bossi I, Sun B, Del Rosso A, Ungar A, . 110. Forleo C, Guida P, Iacoviello M, Resta M, Monitillo F, Sorrentino S, Favale S. Grossman S, D’Ascenzo F, Quinn J, McDermott D, Sheldon R, Furlan R. . Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. Int J Syncope risk stratification tools vs clinical judgment: an individual patient data . Cardiol 2013;168:27–35. meta-analysis. Am J Med 2014;127:1126.e13–25. . 111. Parry SW, Gray JC, Newton JL, Reeve P, O’Shea D, Kenny RA. ‘Front-loaded‘ . 87. Canzoniero JV, Afshar E, Hedian H, Koch C, Morgan DJ. Unnecessary hospital- . head-up tilt table testing: validation of a rapid first line nitrate-provoked tilt pro- ization and related harm for patients with low-risk syncope. JAMA Intern Med . tocol for the diagnosis of vasovagal syncope. Age Ageing 2008;37:411–415. 2015;175:1065–1067. . 112. Verheyden B, Gisolf J, Beckers F, Karemaker JM, Wesseling KH, Aubert AE, 88. Thiruganasambandamoorthy V, Kwong K, Wells GA, Sivilotti ML, Mukarram M, . Wieling W. Impact of age on the vasovagal response provoked by sublingual Rowe BH, Lang E, Perry JJ, Sheldon R, Stiell IG, Taljaard M. Development of the . nitroglycerine in routine tilt testing. Clin Sci (Lond) 2007;113:329–337. .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 62 ESC Guidelines
. 113. Nilsson D, Sutton R, Tas W, Burri P, Melander O, Fedorowski A. Orthostatic . 135. Brignole M, Menozzi C, Gianfranchi L, Oddone D, Lolli G, Bertulla A. Neurally changes in hemodynamics and cardiovascular biomarkers in dysautonomic . mediated syncope detected by carotid sinus massage and head-up tilt test in . patients. PLoS One 2015;10:e0128962. . sick sinus syndrome. Am J Cardiol 1991;68:1032–1036. 114. Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome . 136. Alboni P, Menozzi C, Brignole M, Paparella N, Lolli G, Oddone D, Dinelli M. An (POTS). J Cardiovasc Electrophysiol 2009;20:352–358. . abnormal neural reflex plays a role in causing syncope in sinus bradycardia. JAm . 115. Petersen ME, Williams TR, Sutton R. Psychogenic syncope diagnosed by pro- . Coll Cardiol 1993;22:1130–1134. longed head-up tilt testing. QJM 1995;88:209–213. . 137. Zaidi A, Clough P, Cooper P, Scheepers B, Fitzpatrick AP. Misdiagnosis of epi- 116. Tannemaat MR, van Niekerk J, Reijntjes RH, Thijs RD, Sutton R, van Dijk JG. . lepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol The semiology of tilt-induced psychogenic pseudosyncope. Neurology . 2000;36:181–184. 2013;81:752–758. . 138. Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between 117. Blad H, Lamberts RJ, van Dijk GJ, Thijs RD. Tilt-induced vasovagal syncope and . supine hypertension and orthostatic hypotension in autonomic failure. psychogenic pseudosyncope: Overlapping clinical entities. Neurology . Hypertension 2003;42:136–142. . 2015;85:2006–2010. . 139. Novak P. Assessment of sympathetic index from the Valsalva maneuver. 118. Moya A, Permanyer-Miralda G, Sagrista-Sauleda J, Carne X, Rius T, Mont L, . Neurology 2011;76:2010–2016. Soler-Soler J. Limitations of head-up tilt test for evaluating the efficacy of thera- . 140. Fanciulli A, Strano S, Ndayisaba JP, Goebel G, Gioffre L, Rizzo M, Colosimo C, peutic interventions in patients with vasovagal syncope: results of a controlled . Caltagirone C, Poewe W, Wenning GK, Pontieri FE. Detecting nocturnal hyper- . study of etilefrine versus placebo. J Am Coll Cardiol 1995;25:65–69. . tension in Parkinson’s disease and multiple system atrophy: proposal of a 119. Brignole M, Croci F, Menozzi C, Solano A, Donateo P, Oddone D, Puggioni E, . decision-support algorithm. J Neurol 2014;261:1291–1299. Lolli G. Isometric arm counter-pressure maneuvers to abort impending vasova- . 141. Jones PK, Gibbons CH. The role of autonomic testing in syncope. Auton gal syncope. J Am Coll Cardiol 2002;40:2053–2059. . Neurosci 2014;184:40–45. . 120. Krediet CT, van Dijk N, Linzer M, van Lieshout JJ, Wieling W. Management of . 142. Baschieri F, Calandra-Buonaura G, Doria A, Mastrolilli F, Palareti A, Barletta G, vasovagal syncope: controlling or aborting faints by leg crossing and muscle . Solieri L, Guaraldi P, Martinelli P, Cortelli P. Cardiovascular autonomic testing per- tensing. Circulation 2002;106:1684–1689. . formed with a new integrated instrumental approach is useful in differentiating . 121. van Dijk N, Quartieri F, Blanc JJ, Garcia-Civera R, Brignole M, Moya A, Wieling . MSA-P from PD at an early stage. Parkinsonism Relat Disord 2015;21:477–482. W, PCTrial Investigators. Effectiveness of physical counterpressure maneuvers . 143. Rocchi C, Pierantozzi M, Galati S, Chiaravalloti A, Pisani V, Prosperetti C, in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres . Lauretti B, Stampanoni Bassi M, Olivola E, Schillaci O, Stefani A. Autonomic Trial (PC-Trial). J Am Coll Cardiol 2006;48:1652–1657. . function tests and MIBG in Parkinson’s disease: correlation to disease duration 122. Deharo JC, Jego C, Lanteaume A, Djiane P. An implantable loop recorder study . and motor symptoms. CNS Neurosci Ther 2015;21:727–732. of highly symptomatic vasovagal patients: the heart rhythm observed during a . 144. Kim AJ, Frishman WH. Laughter-induced syncope. Cardiol Rev spontaneous syncope is identical to the recurrent syncope but not correlated . 2012;20:194–196. . with the head-up tilt test or adenosine triphosphate test. J Am Coll Cardiol . 145. Ndayisaba JP, Fanciulli A, Granata R, Duerr S, Hintringer F, Goebel G, Krismer 2006;47:587–593. . F, Wenning GK. Sex and age effects on cardiovascular autonomic function in 123. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, . healthy adults. Clin Auton Res 2015;25:317–326. Andresen D, Benditt DG, Grovale N, De Santo T, Vardas P, International Study . 146. Bonuccelli U, Lucetti C, Del Dotto P, Ceravolo R, Gambaccini G, Bernardini S, . on Syncope of Uncertain Etiology 2 (ISSUE 2) Group. Lack of correlation . Rossi G, Piaggesi A. Orthostatic hypotension in de novo Parkinson disease. Arch between the responses to tilt testing and adenosine triphosphate test and the . Neurol 2003;60:1400–1404. mechanism of spontaneous neurally mediated syncope. Eur Heart J . 147. Struhal W, Javor A, Brunner C, Benesch T, Schmidt V, Vosko MR, Ransmayr G. 2006;27:2232–2239. . The phoenix from the ashes: cardiovascular autonomic dysfunction in behavio- 124. Flevari P, Leftheriotis D, Komborozos C, Fountoulaki K, Dagres N, Theodorakis . ral variant of frontotemporal dementia. J Alzheimers Dis 2014;42:1041–1046. G, Kremastinos D. Recurrent vasovagal syncope: comparison between clomipr- . 148. Parati G, Stergiou G, O’Brien E, Asmar R, Beilin L, Bilo G, Clement D, de la amine and nitroglycerin as drug challenges during head-up tilt testing. Eur Heart . Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA, Imai Y, Kario K, . J 2009;30:2249–2253. . Lurbe E, Mallion JM, Mancia G, Mengden T, Myers M, Ogedegbe G, Ohkubo T, 125. Petersen ME, Williams TR, Gordon C, Chamberlain-Webber R, Sutton R. The . Omboni S, Palatini P, Redon J, Ruilope LM, Shennan A, Staessen JA, normal response to prolonged passive head up tilt testing. Heart . vanMontfrans G, Verdecchia P, Waeber B, Wang J, Zanchetti A, Zhang Y, 2000;84:509–514. . European Society of Hypertension Working Group on Blood Pressure . 126. Furukawa T, Maggi R, Solano A, Croci F, Brignole M. Effect of clinical triggers . Monitoring and Cardiovascular Variability. European Society of Hypertension on positive responses to tilt-table testing potentiated with nitroglycerin or clo- . practice guidelines for ambulatory blood pressure monitoring. J Hypertens mipramine. Am J Cardiol 2011;107:1693–1697. . 2014;32:1359–1366. 127. Petix NR, Del Rosso A, Furlan R, Guarnaccia V, Zipoli A. Nitrate-potentiated . 149. Schmidt C, Berg D, Herting, Prieur S, Junghanns S, Schweitzer K, Globas C, . head-up tilt testing (HUT) has a low diagnostic yield in patients with likely vaso- . Schols L, Reichmann H, Ziemssen T. Loss of nocturnal blood pressure fall in vagal syncope. Pacing Clin Electrophysiol 2014;37:164–172. . various extrapyramidal syndromes. Mov Disord 2009;24:2136–2142. 128. Raviele A, Menozzi C, Brignole M, Gasparini G, Alboni P, Musso G, Lolli G, . 150. Voichanski S, Grossman C, Leibowitz A, Peleg E, Koren-Morag N, Sharabi Y, . Oddone D, Dinelli M, Mureddu R. Value of head-up tilt testing potentiated with . Shamiss A, Grossman E. Orthostatic hypotension is associated with nocturnal sublingual nitroglycerin to assess the origin of unexplained syncope. Am J Cardiol . change in systolic blood pressure. Am J Hypertens 2012;25:159–164. 1995;76:267–272. . 151. Fanciulli A, Strano S, Colosimo C, Caltagirone C, Spalletta G, Pontieri FE. The 129. Ungar A, Sgobino P, Russo V, Vitale E, Sutton R, Melissano D, Beiras X, Bottoni . potential prognostic role of cardiovascular autonomic failure in alpha-synuclei- N, Ebert HH, Gulizia M, Jorfida M, Moya A, Andresen D, Grovale N, Brignole . nopathies. Eur J Neurol 2013;20:231–235. M, International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) . 152. Stuebner E, Vichayanrat E, Low DA, Mathias CJ, Isenmann S, Haensch CA. Investigators. Diagnosis of neurally mediated syncope at initial evaluation and . Twenty-four hour non-invasive ambulatory blood pressure and heart rate mon- . with tilt table testing compared with that revealed by prolonged ECG monitor- . itoring in Parkinson’s disease. Front Neurol 2013;4:49. ing. An analysis from the Third International Study on Syncope of Uncertain . 153. Norcliffe-Kaufmann L, Kaufmann H. Is ambulatory blood pressure monitoring Etiology (ISSUE-3). Heart 2013;99:1825–1831. . useful in patients with chronic autonomic failure? Clin Auton Res 130. Brignole M, Gianfranchi L, Menozzi C, Raviele A, Oddone D, Lolli G, Bottoni N. . 2014;24:189–192. . Role of autonomic reflexes in syncope associated with paroxysmal atrial fibrilla- . 154. Tannemaat MR, Thijs RD, van Dijk JG. Managing psychogenic pseudosyncope: tion. J Am Coll Cardiol 1993;22:1123–1129. . facts and experiences. Cardiol J 2014;21:658–664. 131. Leitch JW, Klein GJ, Yee R, Leather RA, Kim YH. Syncope associated with . 155. Braune S, Auer A, Schulte-Monting J, Schwerbrock S, Lucking CH. supraventricular tachycardia. An expression of tachycardia rate or vasomotor . Cardiovascular parameters: sensitivity to detect autonomic dysfunction and response? Circulation 1992;85:1064–1071. . influence of age and sex in normal subjects. Clin Auton Res 1996;6:3–15. 132. Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of . 156. Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O’Brien PC, Slezak JM. Effect tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J . of age and gender on sudomotor and cardiovagal function and blood pressure . 2014;35:2211–2212. . response to tilt in normal subjects. Muscle Nerve 1997;20:1561–1568. 133. Taneja I, Marney A, Robertson D. Aortic stenosis and autonomic dysfunction: . 157. Barnett SR, Morin RJ, Kiely DK, Gagnon M, Azhar G, Knight EL, Nelson JC, co-conspirators in syncope. Am J Med Sci 2004;327:281–283. . Lipsitz LA. Effects of age and gender on autonomic control of blood pressure 134. Thomson HL, Morris-Thurgood J, Atherton J, Frenneaux M. Reduced cardiopul- . dynamics. Hypertension 1999;33:1195–1200. monary baroreflex sensitivity in patients with hypertrophic cardiomyopathy. . 158. Chiu DT, Shapiro NI, Sun BC, Mottley JL, Grossman SA. Are echocardiography, J Am Coll Cardiol 1998;31:1377–1382. . telemetry, ambulatory electrocardiography monitoring, and cardiac enzymes in
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 63
. emergency department patients presenting with syncope useful tests? A pre- . Documents Committee. Indications for the use of diagnostic implantable and liminary investigation. J Emerg Med 2014;47:113–118. . external ECG loop recorders. Europace 2009;11:671–687. . 159. Benezet-Mazuecos J, Ibanez B, Rubio JM, Navarro F, Martin E, Romero J, Farre J. . 180. Menozzi C, Brignole M, Garcia-Civera R, Moya A, Botto G, Tercedor L, Utility of in-hospital cardiac remote telemetry in patients with unexplained syn- . Migliorini R, Navarro X, International Study on Syncope of Uncertain Etiology cope. Europace 2007;9:1196–1201. . (ISSUE) Investigators. Mechanism of syncope in patients with heart disease and . 160. Croci F, Brignole M, Alboni P, Menozzi C, Raviele A, Del Rosso A, Dinelli M, . negative electrophysiologic test. Circulation 2002;105:2741–2745. Solano A, Bottoni N, Donateo P. The application of a standardized strategy of . 181. Linker NJ, Voulgaraki D, Garutti C, Rieger G, Edvardsson N, PICTURE Study evaluation in patients with syncope referred to three syncope units. Europace . Investigators. Early versus delayed implantation of a loop recorder in patients 2002;4:351–355. . with unexplained syncope–effects on care pathway and diagnostic yield. Int J 161. Bass EB, Curtiss EI, Arena VC, Hanusa BH, Cecchetti A, Karpf M, Kapoor WN. . Cardiol 2013;170:146–151. The duration of Holter monitoring in patients with syncope. Is 24 hours . 182. Edvardsson N, Frykman V, van Mechelen R, Mitro P, Mohii-Oskarsson A, enough? Arch Intern Med 1990;150:1073–1078. . Pasquie JL, Ramanna H, Schwertfeger F, Ventura R, Voulgaraki D, Garutti C, . 162. Rockx MA, Hoch JS, Klein GJ, Yee R, Skanes AC, Gula LJ, Krahn AD. Is ambula- . Stolt P, Linker NJ, PICTURE Study Investigators. Use of an implantable loop tory monitoring for “community-acquired” syncope economically attractive? A . recorder to increase the diagnostic yield in unexplained syncope: results from cost-effectiveness analysis of a randomized trial of external loop recorders ver- . the PICTURE registry. Europace 2011;13:262–269. sus Holter monitoring. Am Heart J 2005;150:1065. . 183. Lacunza-Ruiz FJ, Moya-Mitjans A, Martinez-Alday J, Baron-Esquivias G, Ruiz- . 163. Kinlay S, Leitch JW, Neil A, Chapman BL, Hardy DB, Fletcher PJ. Cardiac event . Granell R, Rivas-Gandara N, Gonzalez-Enriquez S, Leal-del-Ojo J, Arcocha- recorders yield more diagnoses and are more cost-effective than 48-hour . Torres MF, Perez-Villacastin J, Garcia-Heil N, Garcia-Alberola A. Implantable Holter monitoring in patients with palpitations. A controlled clinical trial. Ann . loop recorder allows an etiologic diagnosis in one-third of patients. Results of Intern Med 1996;124:16–20. . the Spanish reveal registry. Circ J 2013;77:2535–2541. . 164. Bruining N, Caiani E, Chronaki C, Guzik P, van der Velde E, Task Force of the . 184. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W, e-Cardiology Working. Acquisition and analysis of cardiovascular signals on . Andresen D, Benditt DG, Vardas P, International Study on Syncope of smartphones: potential, pitfalls and perspectives: by the Task Force of the e- . Uncertain Etiology 2 (ISSUE 2) Group. Early application of an implantable loop . Cardiology Working Group of European Society of Cardiology. Eur J Prev . recorder allows effective specific therapy in patients with recurrent suspected Cardiol 2014;21:4–13. . neurally mediated syncope. Eur Heart J 2006;27:1085–1092. 165. Waks JW, Fein AS, Das S. Wide complex tachycardia recorded with a smart- . 185. Brignole M, Menozzi C, Moya A, Andresen D, Blanc JJ, Krahn AD, Wieling W, phone cardiac rhythm monitor. JAMA Intern Med 2015;175:437–439. . Beiras X, Deharo JC, Russo V, Tomaino M, Sutton R, International Study on . 166. Locati ET, Moya A, Oliveira M, Tanner H, Willems R, Lunati M, Brignole M. . Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in External prolonged electrocardiogram monitoring in unexplained syncope and . patients with neurally mediated syncope and documented asystole: Third palpitations: results of the SYNARR-Flash study. Europace 2016;18:1265–1272. . International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized . :2566–2571. 167. Linzer M, Pritchett EL, Pontinen M, McCarthy E, Divine GW. Incremental diag- . trial. Circulation 2012;125 nostic yield of loop electrocardiographic recorders in unexplained syncope. Am . 186. Brignole M, Ammirati F, Arabia F, Quartieri F, Tomaino M, Ungar A, Lunati M, J Cardiol 1990;66:214–219. . Russo V, Del Rosso A, Gaggioli G, Syncope Unit Project (SUP) Two 168. Schuchert A, Maas R, Kretzschmar C, Behrens G, Kratzmann I, Meinertz T. . Investigators. Assessment of a standardized algorithm for cardiac pacing in older . Diagnostic yield of external electrocardiographic loop recorders in patients . patients affected by severe unpredictable reflex syncopes. Eur Heart J with recurrent syncope and negative tilt table test. Pacing Clin Electrophysiol . 2015;36:1529–1535. 2003;26:1837–1840. . 187. Brignole M, Menozzi C, Moya A, Garcia-Civera R, Mont L, Alvarez M, Errazquin 169. Drak-Hern andez Y, Toquero-Ramos J, Fern andez JM, Pe´rez-Pereira E, Castro- . F, Beiras J, Bottoni N, Donateo P, International Study on Syncope of Uncertain Urda V, Fern andez-Lozano I. Effectiveness and safety of remote monitoring of . Etiology (ISSUE) Investigators. Mechanism of syncope in patients with bundle patients with an implantable loop recorder. Rev Esp Cardiol (Engl Ed) . branch block and negative electrophysiological test. Circulation 2013;66:943–948. . 2001;104:2045–2050. . 170. Furukawa T, Maggi R, Bertolone C, Ammirati F, Santini M, Ricci R, Giada F, . 188. Moya A, Garcia-Civera R, Croci F, Menozzi C, Brugada J, Ammirati F, Del Brignole M. Effectiveness of remote monitoring in the management of syncope . Rosso A, Bellver-Navarro A, Garcia-Sacristan J, Bortnik M, Mont L, Ruiz-Granell and palpitations. Europace 2011;13:431–437. . R, Navarro X, Bradycardia detection in Bundle Branch Block (B4) study. 171. Rothman SA, Laughlin JC, Seltzer J, Walia JS, Baman RI, Siouffi SY, Sangrigoli . Diagnosis, management, and outcomes of patients with syncope and bundle . RM, Kowey PR. The diagnosis of cardiac arrhythmias: a prospective multi- . branch block. Eur Heart J 2011;32:1535–1541. center randomized study comparing mobile cardiac outpatient telemetry versus . 189. Ho RT, Wicks T, Wyeth D, Nei M. Generalized tonic-clonic seizures detected standard loop event monitoring. J Cardiovasc Electrophysiol 2007;18:241–247. . by implantable loop recorder devices: diagnosing more than cardiac arrhyth- 172. Farwell DJ, Freemantle N, Sulke N. The clinical impact of implantable loop . mias. Heart Rhythm 2006;3:857–861. . recorders in patients with syncope. Eur Heart J 2006;27:351–356. . 190. Petkar S, Hamid T, Iddon P, Clifford A, Rice N, Claire R, McKee D, Curtis N, 173. Krahn AD, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope . Cooper PN, Fitzpatrick AP. Prolonged implantable electrocardiographic moni- trial: conventional diagnostic testing versus a prolonged monitoring strategy. . toring indicates a high rate of misdiagnosis of epilepsy–REVISE study. Europace . Circulation 2001;104:46–51. . 2012;14:1653–1660. 174. Da Costa A, Defaye P, Romeyer-Bouchard C, Roche F, Dauphinot V, Deharo . 191. Maggi R, Rafanelli M, Ceccofiglio A, Solari D, Brignole M, Ungar A. Additional JC, Jacon P, Lamaison D, Bathelemy JC, Isaaz K, Laurent G. Clinical impact of . diagnostic value of implantable loop recorder in patients with initial diagnosis of the implantable loop recorder in patients with isolated syncope, bundle branch . real or apparent transient loss of consciousness of uncertain origin. Europace block and negative workup: a randomized multicentre prospective study. Arch . 2014;16:1226–1230. Cardiovasc Dis 2013;106:146–154. . 192. Armstrong VL, Lawson J, Kamper AM, Newton J, Kenny RA. The use of an 175. Podoleanu C, DaCosta A, Defaye P, Taieb J, Galley D, Bru P, Maury P, Mabo P, . implantable loop recorder in the investigation of unexplained syncope in older . Boveda S, Cellarier G, Anselme F, Kouakam C, Delarche N, Deharo JC, FRESH . people. Age Ageing 2003;32:185–188. investigators. Early use of an implantable loop recorder in syncope evaluation: a . 193. Ryan DJ, Nick S, Colette SM, Roseanne K. Carotid sinus syndrome, should we randomized study in the context of the French healthcare system (FRESH . pace? A multicentre, randomised control trial (Safepace 2). Heart study). Arch Cardiovasc Dis 2014;107:546–552. . 2010;96:347–351. . 176. Sulke N, Sugihara C, Hong P, Patel N, Freemantle N. The benefit of a remotely . 194. Bhangu J, McMahon CG, Hall P, Bennett K, Rice C, Crean P, Sutton R, Kenny monitored implantable loop recorder as a first line investigation in unexplained . RA. Long-term cardiac monitoring in older adults with unexplained falls and syncope: the EaSyAS II trial. Europace 2016;18:912–918. . syncope. Heart 2016;102:681–686. 177. Edvardsson N, Garutti C, Rieger G, Linker NJ, PICTURE Study Investigators. . 195. Krahn AD, Klein GJ, Norris C, Yee R. The etiology of syncope in patients Unexplained syncope: implications of age and gender on patient characteristics . with negative tilt table and electrophysiological testing. Circulation and evaluation, the diagnostic yield of an implantable loop recorder, and the . 1995;92:1819–1824. subsequent treatment. Clin Cardiol 2014;37:618–625. . 196. Krahn AD, Klein GJ, Yee R, Takle-Newhouse T, Norris C. Use of an extended . 178. Edvardsson N, Wolff C, Tsintzos S, Rieger G, Linker NJ. Costs of unstructured . monitoring strategy in patients with problematic syncope. Reveal Investigators. investigation of unexplained syncope: insights from a micro-costing analysis of . Circulation 1999;99:406–410. the observational PICTURE registry. Europace 2015;17:1141–1148. . 197. Krahn AD, Klein GJ, Yee R, Skanes AC. Detection of asymptomatic arrhythmias 179. Brignole M, Vardas P, Hoffman E, Huikuri H, Moya A, Ricci R, Sulke N, Wieling . in unexplained syncope. Am Heart J 2004;148:326–332. W, Auricchio A, Lip GY, Almendral J, Kirchhof P, Aliot E, Gasparini M, . 198. Ermis C, Zhu AX, Pham S, Li JM, Guerrero M, Vrudney A, Hiltner L, Lu F, Braunschweig F, Lip GY, Almendral J, Kirchhof P, Botto GL, EHRA Scientific . Sakaguchi S, Lurie KG, Benditt DG. Comparison of automatic and patient-
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 64 ESC Guidelines
. activated arrhythmia recordings by implantable loop recorders in the evaluation . Antzelevitch C, Allocca G, Priori SG, Lubitz SA. Programmed ventricular stimu- of syncope. Am J Cardiol 2003;92:815–819. . lation for risk stratification in the Brugada syndrome: a pooled analysis. . 199. Moya A, Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Wieling W, . Circulation 2016;133:622–630. Andresen D, Benditt DG, Garcia-Sacristan JF, Beiras X, Grovale N, Vardas P, . 221. Scheinman MM, Peters RW, Suave MJ, Desai J, Abbott JA, Cogan J, Wohl B, International Study on Syncope of Uncertain Etiology 2 (ISSUE 2) . Williams K. Value of the H-Q interval in patients with bundle branch block and . Group. Reproducibility of electrocardiographic findings in patients with . the role of prophylactic permanent pacing. Am J Cardiol 1982;50:1316–1322. suspected reflex neurally-mediated syncope. Am J Cardiol . 222. Blomstro¨m-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm 2008;102:1518–1523. . AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer CW Jr, 200. Sud S, Klein GJ, Skanes AC, Gula LJ, Yee R, Krahn AD. Implications of mecha- . Stevenson WG, Tomaselli GF, Antman EM, Smith SC Jr, Alpert JS, Faxon DP, nism of bradycardia on response to pacing in patients with unexplained syn- . Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell cope. Europace 2007;9:312–318. . RO Jr, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia 201. Olmos C, Franco E, Suarez-Barrientos A, Fortuny E, Martin-Garcia A, Viliani D, . MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, . Macaya C, Perez de Isla L. Wearable wireless remote monitoring system: an . Trappe HJ, American College of Cardiology, American Heart Association Task alternative for prolonged electrocardiographic monitoring. Int J Cardiol . Force on Practice Guidelines, European Society of Cardiology Committee for 2014;172:e43–44. . Practice Guidelines, Writing Committee to Develop Guidelines for the manage- 202. Moya A, Brignole M, Menozzi C, Garcia-Civera R, Tognarini S, Mont L, Botto . ment of Patients With Supraventricular Arrhythmias. ACC/AHA/ESC guidelines . G, Giada F, Cornacchia D, International Study on Syncope of . for the management of patients with supraventricular arrhythmias–executive Uncertain Etiology (ISSUE) Investigators. Mechanism of syncope in patients . summary: a report of the American College of Cardiology/American Heart with isolated syncope and in patients with tilt-positive syncope. Circulation . Association Task Force on Practice Guidelines and the European Society of 2001;104:1261–1267. . Cardiology Committee for Practice Guidelines (Writing Committee to . 203. Furukawa T, Maggi R, Bertolone C, Fontana D, Brignole M. Additional diagnostic . Develop Guidelines for the Management of Patients With Supraventricular value of very prolonged observation by implantable loop recorder in patients . Arrhythmias). Circulation 2003;108:1871–1909. with unexplained syncope. J Cardiovasc Electrophysiol 2012;23:67–71. . 223. Pfister R, Hagemeister J, Esser S, Hellmich M, Erdmann E, Schneider CA. NT- . 204. LaFrance WC Jr, Baker GA, Duncan R, Goldstein LH, Reuber M. Minimum . pro-BNP for diagnostic and prognostic evaluation in patients hospitalized for requirements for the diagnosis of psychogenic nonepileptic seizures: a staged . syncope. Int J Cardiol 2012;155:268–272. approach: a report from the International League Against Epilepsy Nonepileptic . 224. Costantino G, Solbiati M, Casazza G, Bonzi M, Vago T, Montano N, Seizures Task Force. Epilepsia 2013;54:2005–2018. . McDermott D, Quinn J, Furlan R. Usefulness of N-terminal pro-B-type natriu- 205. Saal DP, Thijs RD, van Zwet EW, Bootsma M, Brignole M, Benditt DG, van Dijk . retic Peptide increase as a marker for cardiac arrhythmia in patients with syn- JG. Temporal relationship of asystole to onset of transient loss of consciousness . cope. Am J Cardiol 2014;113:98–102. in tilt-induced reflex syncope. JACC: Clinical Electrophysiology 2017;3:1592–1598. . 225. Thiruganasambandamoorthy V, Ramaekers R, Rahman MO, Stiell IG, Sikora L, . 206. Whittaker RG. Video telemetry: current concepts and recent advances. Pract . Kelly SL, Christ M, Claret PG, Reed MJ. Prognostic value of cardiac biomarkers Neurol 2015;15:445–450. . in the risk stratification of syncope: a systematic review. Intern Emerg Med 207. Goodwin E, Kandler RH, Alix JJ. The value of home video with ambulatory . 2015;10:1003–1014. EEG: a prospective service review. Seizure 2014;23:480–482. . 226. Guieu R, Deharo JC, Ruf J, Mottola G, Kipson N, Bruzzese L, Gerolami V, . 208. Stephenson J, Breningstall G, Steer C, Kirkpatrick M, Horrocks I, Nechay A, . Franceschi F, Ungar A, Tomaino M, Iori M, Brignole M. Adenosine and Zuberi S. Anoxic-epileptic seizures: home video recordings of epileptic seizures . clinical forms of neurally-mediated syncope. J Am Coll Cardiol induced by syncopes. Epileptic Disord 2004;6:15–19. . 2015;66:204–205. 209. Linzer M, Yang EH, Estes NA III, Wang P, Vorperian VR, Kapoor WN. . 227. Flammang D, Church TR, De Roy L, Blanc JJ, Leroy J, Mairesse GH, Otmani A, Diagnosing syncope. Part 2: Unexplained syncope. Clinical Efficacy Assessment . Graux PJ, Frank R, Purnode P, ATP Multicenter Study. Treatment of unex- Project of the American College of Physicians. Ann Intern Med 1997;127:76–86. . plained syncope: a multicenter, randomized trial of cardiac pacing guided by 210. Dhingra RC. Sinus node dysfunction. Pacing Clin Electrophysiol . adenosine 5’-triphosphate testing. Circulation 2012;125:31–36. . 1983;6:1062–1069. . 228. Brignole M, Gaggioli G, Menozzi C, Gianfranchi L, Bartoletti A, Bottoni N, Lolli 211. Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients . G, Oddone D, Del Rosso A, Pellinghelli G. Adenosine-induced atrioventricular with sinus bradycardia: a long-term follow-up study. Ann Intern Med . block in patients with unexplained syncope: the diagnostic value of ATP testing. 1979;90:24–29. . Circulation 1997;96:3921–3927. . 212. Menozzi C, Brignole M, Alboni P, Boni L, Paparella N, Gaggioli G, Lolli G. The . 229. Donateo P, Brignole M, Menozzi C, Bottoni N, Alboni P, Dinelli M, Del Rosso natural course of untreated sick sinus syndrome and identification of the varia- . A, Croci F, Oddone D, Solano A, Puggioni E. Mechanism of syncope in patients bles predictive of unfavorable outcome. Am J Cardiol 1998;82:1205–1209. . with positive adenosine triphosphate tests. J Am Coll Cardiol 2003;41:93–98. 213. McAnulty JH, Rahimtoola SH, Murphy E, DeMots H, Ritzmann L, Kanarek PE, . 230. Krishnan B, Patarroyo-Aponte M, Duprez D, Pritzker M, Missov E, Benditt DG. . Kauffman S. Natural history of “high-risk” bundle-branch block: final report of a . Orthostatic hypotension of unknown cause: unanticipated association with ele- prospective study. N Engl J Med 1982;307:137–143. . vated circulating N-terminal brain natriuretic peptide (NT-proBNP). Heart 214. Gronda M, Magnani A, Occhetta E, Sauro G, D’Aulerio M, Carfora A, Rossi P. . Rhythm 2015;12:1287–1294. . Electrophysiological study of atrio-ventricular block and ventricular conduction . 231. Fedorowski A, Burri P, Struck J, Juul-Moller S, Melander O. Novel cardiovascu- defects. Prognostic and therapeutical implications. G Ital Cardiol . lar biomarkers in unexplained syncopal attacks: the SYSTEMA cohort. J Intern 1984;14:768–773. . Med 2013;273:359–367. 215. Bergfeldt L, Edvardsson N, Rosenqvist M, Vallin H, Edhag O. Atrioventricular . 232. Li H, Kem DC, Reim S, Khan M, Vanderlinde-Wood M, Zillner C, Collier D, block progression in patients with bifascicular block assessed by repeated elec- . Liles C, Hill MA, Cunningham MW, Aston CE, Yu X. Agonistic autoantibodies trocardiography and a bradycardia-detecting pacemaker. Am J Cardiol . as vasodilators in orthostatic hypotension: a new mechanism. Hypertension 1994;74:1129–1132. . 2012;59:402–408. . 216. Kaul U, Dev V, Narula J, Malhotra AK, Talwar KK, Bhatia ML. Evaluation of . 233. Li H, Yu X, Liles C, Khan M, Vanderlinde-Wood M, Galloway A, Zillner C, patients with bundle branch block and “unexplained” syncope: a study based . Benbrook A, Reim S, Collier D, Hill MA, Raj SR, Okamoto LE, Cunningham on comprehensive electrophysiologic testing and ajmaline stress. Pacing Clin . MW, Aston CE, Kem DC. Autoimmune basis for postural tachycardia syn- Electrophysiol 1988;11:289–297. . drome. J Am Heart Assoc 2014;3:e000755. . 217. Kalscheur MM, Donateo P, Wenzke KE, Aste M, Oddone D, Solano A, Maggi R, . 234. Fedorowski A, Li H, Yu X, Koelsch KA, Harris VM, Liles C, Murphy TA, Quadri Croci F, Page RL, Brignole M, Hamdan MH. Long-term outcome of patients . SMS, Scofield RH, Sutton R, Melander O, Kem DC. Antiadrenergic autoimmun- with bifascicular block and unexplained syncope following cardiac pacing. Pacing . ity in postural tachycardia syndrome. Europace 2017;19:1211–1219. Clin Electrophysiol 2016;39:1126–1131. . 235. Recchia D, Barzilai B. Echocardiography in the evaluation of patients with syn- 218. Olshansky B, Hahn EA, Hartz VL, Prater SP, Mason JW. Clinical significance of . cope. J Gen Intern Med 1995;10:649–655. syncope in the electrophysiologic study versus electrocardiographic monitoring . 236. Sarasin FP, Junod AF, Carballo D, Slama S, Unger PF, Louis-Simonet M. Role of (ESVEM) trial. The ESVEM Investigators. Am Heart J 1999;137:878–886. . echocardiography in the evaluation of syncope: a prospective study. Heart . 219. Link MS, Kim KM, Homoud MK, Estes NA III, Wang PJ. Long-term outcome of . 2002;88:363–367. patients with syncope associated with coronary artery disease and a nondiag- . 237. Hoegholm A, Clementsen P, Mortensen SA. Syncope due to right atrial throm- nostic electrophysiologic evaluation. Am J Cardiol 1999;83:1334–1337. . boembolism: diagnostic importance of two-dimensional echocardiography. Acta 220. Sroubek J, Probst V, Mazzanti A, Delise P, Hevia JC, Ohkubo K, Zorzi A, . Cardiol 1987;42:469–473. Champagne J, Kostopoulou A, Yin X, Napolitano C, Milan DJ, Wilde A, Sacher . 238. Omran H, Fehske W, Rabahieh R, Hagendorff A, Pizzulli L, Zirbes M, Luderitz F, Borggrefe M, Ellinor PT, Theodorakis G, Nault I, Corrado D, Watanabe I, . B. Valvular aortic stenosis: risk of syncope. J Heart Valve Dis 1996;5:31–34.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 65
. 239. Bogaert AM, De Scheerder I, Colardyn F. Successful treatment of aortic rupture . 263. Kim KH, Cho JG, Lee KO, Seo TJ, Shon CY, Lim SY, Yun KH, Sohn IS, Hong YJ, . presenting as a syncope: the role of echocardiography in diagnosis. Int J Cardiol . Park HW, Kim JH, Kim W, Ahn YK, Jeong MH, Park JC, Kang JC. Usefulness of 1987;16:212–214. . physical maneuvers for prevention of vasovagal syncope. Circ J 240. Acikel M, Yekeler I, Ates A, Erkut B. A giant left atrial myxoma: an unusual . 2005;69:1084–1088. . cause of syncope and cerebral emboli. Int J Cardiol 2004;94:325–326. . 264. Tomaino M, Romeo C, Vitale E, Kus T, Moya A, van Dijk N, Giuli S, D’Ippolito 241. Nogueira DC, Bontempo D, Menardi AC, Vicente WV, Ribeiro PJ, Evora PR. . G, Gentili A, Sutton R, International Study on Syncope of Uncertain Etiology 3 Left atrial myxoma as the cause of syncope in an adolescent. Arq Bras Cardiol . (ISSUE 3) Investigators. Physical counter-pressure manoeuvres in preventing 2003;81:206–209, 202–205. . syncopal recurrence in patients older than 40 years with recurrent neurally 242. Sinha AK, Singh BP. LA myxoma presenting as recurrent syncope. Indian Heart J . mediated syncope: a controlled study from the Third International Study on 2013;65:643. . Syncope of Uncertain Etiology (ISSUE-3)†. Europace 2014;16:1515–1520. 243. Rahman MS, Michael H. A rare presentation of chest pain and syncope: massive . 265. Reybrouck T, Heidbuchel H, Van De Werf F, Ector H. Long-term follow-up . right atrial myxoma. Postgrad Med J 2012;88:671–672. . results of tilt training therapy in patients with recurrent neurocardiogenic syn- 244. Han H, Li Y, Guo S, Yu X. Right atrial myxoma-induced syncope. Postgrad Med J . cope. Pacing Clin Electrophysiol 2002;25:1441–1446. 2011;87:438–439. . 266. Zeng H, Ge K, Zhang W, Wang G, Guo L. The effect of orthostatic training in 245. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, . the prevention of vasovagal syncope and its influencing factors. Int Heart J . Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, . 2008;49:707–712. Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, . 267. Jang WJ, Yim HR, Lee SH, Park SJ, Kim JS, On YK. Prognosis after tilt training in Tillmanns C, Watkins H. 2014 ESC Guidelines on diagnosis and management of . patients with recurrent vasovagal syncope. Int J Cardiol 2013;168:4264–4265. hypertrophic cardiomyopathy: the Task Force for the Diagnosis and . 268. Foglia-Manzillo G, Giada F, Gaggioli G, Bartoletti A, Lolli G, Dinelli M, Del . Management of Hypertrophic Cardiomyopathy of the European Society of . Rosso A, Santarone M, Raviele A, Brignole M. Efficacy of tilt training in the Cardiology (ESC). Eur Heart J 2014;35:2733–2779. . treatment of neurally mediated syncope. A randomized study. Europace 246. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, . 2004;6:199–204. . Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a . 269. Kinay O, Yazici M, Nazli C, Acar G, Gedikli O, Altinbas A, Kahraman H, Dogan disease of left ventricular outflow tract obstruction. Circulation 2006;114:2232–2239. . A, Ozaydin M, Tuzun N, Ergene O. Tilt training for recurrent neurocardiogenic 247. Shah JS, Esteban MT, Thaman R, Sharma R, Mist B, Pantazis A, Ward D, Kohli . syncope: effectiveness, patient compliance, and scheduling the frequency of SK, Page SP, Demetrescu C, Sevdalis E, Keren A, Pellerin D, McKenna WJ, . training sessions. Jpn Heart J 2004;45:833–843. Elliott PM. Prevalence of exercise-induced left ventricular outflow tract . 270. On YK, Park J, Huh J, Kim JS. Is home orthostatic self-training effective in pre- obstruction in symptomatic patients with non-obstructive hypertrophic cardio- . venting neurally mediated syncope? Pacing Clin Electrophysiol 2007;30:638–643. myopathy. Heart 2008;94:1288–1294. . 271. Duygu H, Zoghi M, Turk U, Akyuz S, Ozerkan F, Akilli A, Erturk U, Onder R, . 248. Dimitrow PP, Bober M, Michalowska J, Sorysz D. Left ventricular outflow tract . Akin M. The role of tilt training in preventing recurrent syncope in patients gradient provoked by upright position or exercise in treated patients with . with vasovagal syncope: a prospective and randomized study. Pacing Clin hypertrophic cardiomyopathy without obstruction at rest. Echocardiography . Electrophysiol 2008;31:592–596. 2009;26:513–520. . 272. Tan MP, Newton JL, Chadwick TJ, Gray JC, Nath S, Parry SW. Home ortho- . 249. Marwick TH, Nakatani S, Haluska B, Thomas JD, Lever HM. Provocation of . static training in vasovagal syncope modifies autonomic tone: results of a latent left ventricular outflow tract gradients with amyl nitrite and exercise in . randomized, placebo-controlled pilot study. Europace 2010;12:240–246. hypertrophic cardiomyopathy. Am J Cardiol 1995;75:805–809. . 273. Verheyden B, Liu J, van Dijk N, Westerhof BE, Reybrouck T, Aubert AE, 250. Sneddon JF, Scalia G, Ward DE, McKenna WJ, Camm AJ, Frenneaux MP. . Wieling W. Steep fall in cardiac output is main determinant of hypotension dur- Exercise induced vasodepressor syncope. Br Heart J 1994;71:554–557. . ing drug-free and nitroglycerine-induced orthostatic vasovagal syncope. Heart 251. Sakaguchi S, Shultz JJ, Remole SC, Adler SW, Lurie KG, Benditt DG. Syncope . Rhythm 2008;5:1695–1701. associated with exercise, a manifestation of neurally mediated syncope. Am J . 274. Burklow TR, Moak JP, Bailey JJ, Makhlouf FT. Neurally mediated cardiac syn- . Cardiol 1995;75:476–481. . cope: autonomic modulation after normal saline infusion. J Am Coll Cardiol 252. Colivicchi F, Ammirati F, Biffi A, Verdile L, Pelliccia A, Santini M. Exercise- . 1999;33:2059–2066. related syncope in young competitive athletes without evidence of structural . 275. Sheldon R, Raj SR, Rose MS, Morillo CA, Krahn AD, Medina E, Talajic M, Kus T, heart disease. Clinical presentation and long-term outcome. Eur Heart J . Seifer CM, Lelonek M, Klingenheben T, Parkash R, Ritchie D, McRae M, POST 2 . 2002;23:1125–1130. . Investigators. Fludrocortisone for the prevention of vasovagal syncope: a 253. Woelfel AK, Simpson RJ Jr, Gettes LS, Foster JR. Exercise-induced distal atrio- . randomized, placebo-controlled trial. J Am Coll Cardiol 2016;68:1–9. ventricular block. J Am Coll Cardiol 1983;2:578–581. . 276. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing 254. Byrne JM, Marais HJ, Cheek GA. Exercise-induced complete heart block in a . syncope recurrence in children: a double-blind, placebo-controlled, randomized . patient with chronic bifascicular block. J Electrocardiol 1994;27:339–342. . trial. J Am Coll Cardiol 2005;45:484–488. 255. Aste M, Oddone D, Donateo P, Solano A, Maggi R, Croci F, Solari D, Brignole . 277. Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, Moya A. Effect M. Syncope in patients paced for atrioventricular block. Europace . of etilefrine in preventing syncopal recurrence in patients with vasovagal syn- . 2016;18:1735–1739. . cope: a double-blind, randomized, placebo-controlled trial. The Vasovagal 256. Sumiyoshi M, Nakata Y, Yasuda M, Tokano T, Ogura S, Nakazato Y, Yamaguchi . Syncope International Study. Circulation 1999;99:1452–1457. H. Clinical and electrophysiologic features of exercise-induced atrioventricular . 278. Izcovich A, Gonzalez Malla C, Manzotti M, Catalano HN, Guyatt G. Midodrine block. Am Heart J 1996;132:1277–1281. . for orthostatic hypotension and recurrent reflex syncope: a systematic review. . 257. Wissocq L, Ennezat PV, Mouquet F. Exercise-induced high-degree atrioventricu- . Neurology 2014;83:1170–1177. lar block. Arch Cardiovasc Dis 2009;102:733–735. . 279. Madrid AH, Ortega J, Rebollo JG, Manzano JG, Segovia JG, Sanchez A, Pena 258. Anderson LL, Dai D, Miller AL, Roe MT, Messenger JC, Wang TY. . G, Moro C. Lack of efficacy of atenolol for the prevention of neurally medi- Percutaneous coronary intervention for older adults who present with syncope . ated syncope in a highly symptomatic population: a prospective, double- . and coronary artery disease? Insights from the National Cardiovascular Data . blind, randomized and placebo-controlled study. J Am Coll Cardiol Registry. Am Heart J 2016;176:1–9. . 2001;37:554–559. 259. El-Sayed H, Hainsworth R. Salt supplement increases plasma volume and . 280. Sheldon R, Connolly S, Rose S, Klingenheben T, Krahn A, Morillo C, Talajic M, . orthostatic tolerance in patients with unexplained syncope. Heart . Ku T, Fouad-Tarazi F, Ritchie D, Koshman ML, POST Investigators. Prevention 1996;75:134–140. . of Syncope Trial (POST): a randomized, placebo-controlled study of metopro- 260. Solari D, Tesi F, Unterhuber M, Gaggioli G, Ungar A, Tomaino M, Brignole M. . lol in the prevention of vasovagal syncope. Circulation 2006;113:1164–1170. Stop vasodepressor drugs in reflex syncope: a randomised controlled trial. . 281. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects Heart 2017;103:449–455. . of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refrac- 261. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, . tory vasovagal syncope: a randomized, double-blind, placebo-controlled study. Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel . J Am Coll Cardiol 1999;33:1227–1230. . PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, . 282. Theodorakis GN, Markianos M, Zarvalis E, Livanis EG, Flevari P, Kremastinos Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood- . DT. Provocation of neurocardiogenic syncope by clomipramine administration Pressure Control. N Engl J Med 2015;373:2103–2116. . during the head-up tilt test in vasovagal syndrome. J Am Coll Cardiol 262. Brignole M, Menozzi C, Gaggioli G, Musso G, Foglia-Manzillo G, Mascioli G, . 2000;36:174–178. Fradella G, Bottoni N, Mureddu R. Effects of long-term vasodilator therapy in . 283. Marquez MF, Urias-Medina K, Gomez-Flores J, Sobrino A, Sotomayor-Gonzalez patients with carotid sinus hypersensitivity. Am Heart J 1998;136:264–268. . A, Gonzalez-Hermosillo A, Cardenas M. [Comparison of metoprolol vs
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 66 ESC Guidelines
. clonazepam as a first treatment choice among patients with neurocardiogenic . 303. Baron-Esquivias G, Morillo CA, Moya-Mitjans A, Martinez-Alday J, Ruiz-Granell syncope]. Gac Med Mex 2008;144:503–507. . R, Lacunza-Ruiz J, Garcia-Civera R, Gutierrez-Carretero E, Romero-Garrido R. 284. Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Use of octreotide in the . Dual-chamber pacing with closed loop stimulation in recurrent reflex vasovagal . treatment of refractory orthostatic intolerance. Am J Ther 2012;19:7–10. . syncope: the SPAIN Study. J Am Coll Cardiol 2017;70:1720–1728. 285. Brignole M, Solari D, Iori M, Bottoni N, Guieu R, Deharo JC. Efficacy of theo- . 304. Madigan NP, Flaker GC, Curtis JJ, Reid J, Mueller KJ, Murphy TJ. Carotid sinus phylline in patients affected by low adenosine syncope. Heart Rhythm . hypersensitivity: beneficial effects of dual-chamber pacing. Am J Cardiol 2016;13:1151–1154. . 1984;53:1034–1040. 286. Brignole M, Guieu R, Tomaino M, Iori M, Ungar A, Bertolone C, Unterhuber M, . 305. Brignole M, Sartore B, Barra M, Menozzi C, Lolli G. Is DDD superior to VVI Bottoni N, Tesi F, Claude Deharo J. Mechanism of syncope without prodromes . pacing in mixed carotid sinus syndrome? An acute and medium-term study. with normal heart and normal electrocardiogram. Heart Rhythm . Pacing Clin Electrophysiol 1988;11:1902–1910. . 2017;14:234–239. . 306. Sutton R. Pacing in patients with carotid sinus and vasovagal syndromes. Pacing 287. Vaddadi G, Guo L, Esler M, Socratous F, Schlaich M, Chopra R, Eikelis N, . Clin Electrophysiol 1989;12:1260–1263. Lambert G, Trauer T, Lambert E. Recurrent postural vasovagal syncope: sympa- . 307. Palmisano P, Dell’Era G, Russo V, Zaccaria M, Mangia R, Bortnik M, De Vecchi thetic nervous system phenotypes. Circ Arrhythm Electrophysiol 2011;4:711–718. . F, Giubertoni A, Patti F, Magnani A, Nigro G, Rago A, Occhetta E, Accogli M. . 288. Schroeder C, Birkenfeld AL, Mayer AF, Tank J, Diedrich A, Luft FC, Jordan J. . Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. JAm . and occurrence of syncope induced by head-up tilt test in older patients with Coll Cardiol 2006;48:516–522. . refrac\tory cardioinhibitory vasovagal syncope: the Tilt test-Induced REsponse 289. Sheldon RS, Ritchie D, McRae M, Raj S. Norepinephrine transport inhibition for . in Closed-loop Stimulation multicentre, prospective, single blind, randomized . treatment of vasovagal syncope. J Cardiovasc Electrophysiol 2013;24:799–803. . study. Europace; doi:10.1093/europace/eux015. Published online ahead of print 290. Pachon JC, Pachon EI, Cunha Pachon MZ, Lobo TJ, Pachon JC, Santillana TG. . 12 April 2017. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vas- . 308. Russo V, Rago A, Papa AA, Golino P, Calabro R, Russo MG, Nigro G. . ovagal) syncope: cardioneuroablation long-term results. Europace . The effect of dual-chamber closed-loop stimulation on syncope recurrence 2011;13:1231–1242. . in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a 291. Aksu T, Gu¨ler TE, Bozyel S, Ozcan€ KS, Yalin K, Mutluer FO. . prospective, randomised, single-blind, crossover study. Heart 2013;99: Cardioneuroablation in the treatment of neurally mediated reflex syncope: a . 1609–1613. review of the current literature. Turk Kardiyol Dern Ars 2017;45:33–41. . 309. Brignole M, Deharo JC, Menozzi C, Moya A, Sutton R, Tomaino M, Ungar A. 292. Brignole M, Arabia F, Ammirati F, Tomaino M, Quartieri F, Rafanelli M, Del . The benefit of pacemaker therapy in patients with neurally-mediated syncope Rosso A, Rita Vecchi M, Russo V, Gaggioli G, Syncope Unit Project 2 (SUP 2) . and documented asystole: a meta-analysis of implantable loop recorder studies. . investigators. Standardized algorithm for cardiac pacing in older patients . Europace; doi:10.1093/europace/eux321. Published online ahead of print 15 affected by severe unpredictable reflex syncope: 3-year insights from the . December 2017. Syncope Unit Project 2 (SUP 2) study. Europace 2016;18:1427–1433. . 310. Claydon VE, Hainsworth R. Salt supplementation improves orthostatic cerebral 293. Brignole M, Menozzi C. The natural history of carotid sinus syncope and the . and peripheral vascular control in patients with syncope. Hypertension . effect of cardiac pacing. Europace 2011;13:462–464. . 2004;43:809–813. 294. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt . 311. Schroeder C, Bush VE, Norcliffe LJ, Luft FC, Tank J, Jordan J, Hainsworth R. OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, . Water drinking acutely improves orthostatic tolerance in healthy subjects. Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE. 2013 ESC . Circulation 2002;106:2806–2811. . Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task . 312. Zia A, Kamaruzzaman SB, Tan MP. Blood pressure lowering therapy in older Force on cardiac pacing and resynchronization therapy of the European Society . people: does it really cause postural hypotension or falls? Postgrad Med of Cardiology (ESC). Developed in collaboration with the European Heart . 2015;127:186–193. . Rhythm Association (EHRA). Eur Heart J 2013;34:2281–2329. . 313. Verwoert GC, Mattace-Raso FU, Hofman A, Heeringa J, Stricker BH, Breteler 295. Gaggioli G, Brignole M, Menozzi C, Devoto G, Oddone D, Gianfranchi L, . MM, Witteman JC. Orthostatic hypotension and risk of cardiovascular disease Gostoli E, Bottoni N, Lolli G. A positive response to head-up tilt testing pre- . in elderly people: the Rotterdam study. J Am Geriatr Soc 2008;56:1816–1820. dicts syncopal recurrence in carotid sinus syndrome patients with permanent . 314. Kamaruzzaman S, Watt H, Carson C, Ebrahim S. The association between . pacemakers. Am J Cardiol 1995;76:720–722. . orthostatic hypotension and medication use in the British Women’s Heart and 296. Connolly SJ, Sheldon R, Roberts RS, Gent M. The North American Vasovagal . Health Study. Age Ageing 2010;39:51–56. Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the . 315. Valbusa F, Labat C, Salvi P, Vivian ME, Hanon O, Benetos A, PARTAGE investi- prevention of vasovagal syncope. J Am Coll Cardiol 1999;33:16–20. . gators. Orthostatic hypotension in very old individuals living in nursing homes: . 297. Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya A. Dual- . the PARTAGE study. J Hypertens 2012;30:53–60. chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibi- . 316. Romero-Ortuno R, O’Connell MD, Finucane C, Soraghan C, Fan CW, Kenny tory syncope: pacemaker versus no therapy: a multicenter randomized study. . RA. Insights into the clinical management of the syndrome of supine . The Vasovagal Syncope International Study (VASIS) Investigators. Circulation . hypertension–orthostatic hypotension (SH-OH): the Irish Longitudinal Study 2000;102:294–299. . on Ageing (TILDA). BMC Geriatr 2013;13:73. 298. Ammirati F, Colivicchi F, Santini M, Syncope Diagnosis and Treatment Study . 317. Canney M, O’Connell MD, Murphy CM, O’Leary N, Little MA, O’Seaghdha CM, Investigators. Permanent cardiac pacing versus medical treatment for the pre- . Kenny RA. Single agent antihypertensive therapy and orthostatic blood pressure vention of recurrent vasovagal syncope: a multicenter, randomized, controlled . behaviour in older adults using beat-to-beat measurements: the Irish trial. Circulation 2001;104:52–57. . Longitudinal Study on Ageing. PLoS One 2016;11:e0146156. 299. Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, . 318. Fogari R, Zoppi A, Mugellini A, Corradi L, Lazzari P, Preti P, Derosa G. Efficacy . Morillo C, Gent M, VPS II Investigators. Pacemaker therapy for prevention of . and safety of two treatment combinations of hypertension in very elderly syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal . patients. Arch Gerontol Geriatr 2009;48:401–405. Pacemaker Study (VPS II): a randomized trial. JAMA 2003;289:2224–2229. . 319. van Lieshout JJ, ten Harkel AD, Wieling W. Physical manoeuvres for combating 300. Raviele A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R, . orthostatic dizziness in autonomic failure. Lancet 1992;339:897–898. . Brignole M, Vasovagal Syncope and Pacing Trial Investigators. A randomized, . 320. Smit AA, Wieling W, Fujimura J, Denq JC, Opfer-Gehrking TL, Akarriou M, double-blind, placebo-controlled study of permanent cardiac pacing for the . Karemaker JM, Low PA. Use of lower abdominal compression to combat treatment of recurrent tilt-induced vasovagal syncope. The Vasovagal Syncope . orthostatic hypotension in patients with autonomic dysfunction. Clin Auton Res and Pacing Trial (SYNPACE). Eur Heart J 2004;25:1741–1748. . 2004;14:167–175. 301. Sud S, Massel D, Klein GJ, Leong-Sit P, Yee R, Skanes AC, Gula LJ, Krahn AD. . 321. Fanciulli A, Goebel G, Metzler B, Sprenger F, Poewe W, Wenning GK, Seppi K. The expectation effect and cardiac pacing for refractory vasovagal syncope. Am . Elastic abdominal binders attenuate orthostatic hypotension in Parkinson’s dis- J Med 2007;120:54–62. . ease. Mov Dis Clin Practice 2015;3:156–160. . 302. Brignole M, Donateo P, Tomaino M, Massa R, Iori M, Beiras X, Moya A, Kus T, . 322. Ten Harkel AD, Van Lieshout JJ, Wieling W. Treatment of orthostatic hypoten- Deharo JC, Giuli S, Gentili A, Sutton R, International Study on Syncope of . sion with sleeping in the head-up tilt position, alone and in combination with Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in . fludrocortisone. J Intern Med 1992;232:139–145. patients with presumed neurally mediated syncope and documented asystole is . 323. Omboni S, Smit AA, van Lieshout JJ, Settels JJ, Langewouters GJ, Wieling W. greater when tilt test is negative: an analysis from the third International Study . Mechanisms underlying the impairment in orthostatic tolerance after nocturnal on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol . recumbency in patients with autonomic failure. Clin Sci (Lond) 2001;101: 2014;7:10–16. . 609–618.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 67
. 324. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, . 346. Morady F, Higgins J, Peters RW, Schwartz AB, Shen EN, Bhandari A, Scheinman Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a double-blind, placebo- . MM, Sauve MJ. Electrophysiologic testing in bundle branch block and unex- . controlled study with midodrine. Am J Med 1993;95:38–48. . plained syncope. Am J Cardiol 1984;54:587–591. 325. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of . 347. Tabrizi F, Rosenqvist M, Bergfeldt L, Englund A. Long-term prognosis in patients midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, . with bifascicular block–the predictive value of noninvasive and invasive assess- . double-blind multicenter study. Midodrine Study Group. JAMA 1997;277: . ment. J Intern Med 2006;260:31–38. 1046–1051. . 348. Ruwald MH, Okumura K, Kimura T, Aonuma K, Shoda M, Kutyifa V, Ruwald 326. Wright RA, Kaufmann HC, Perera R, Opfer-Gehrking TL, McElligott MA, Sheng . AC, McNitt S, Zareba W, Moss AJ. Syncope in high-risk cardiomyopathy KN, Low PA. A double-blind, dose-response study of midodrine in neurogenic . patients with implantable defibrillators: frequency, risk factors, mechanisms, and orthostatic hypotension. Neurology 1998;51:120–124. . association with mortality: results from the multicenter automatic defibrillator 327. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the . implantation trial-reduce inappropriate therapy (MADIT-RIT) study. Circulation head-up position limit the postural decrease in cardiac output in autonomic fail- . 2014;129:545–552. . ure. Clin Auton Res 2000;10:35–42. . 349. Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y, Marquie C, 328. Finke J, Sagemuller I. [Fludrocortisone in the treatment of orthostatic hypoten- . Rosa A, Diallo A, Cassagneau R, Loizeau C, Martins R, Field ME, Derval N, sion: ophthalmodynamography during standing(author’s transl)]. Dtsch Med . Miyazaki S, Denis A, Nogami A, Ritter P, Gourraud JB, Ploux S, Rollin A, Wochenschr 1975;100:1790–1792. . Zemmoura A, Lamaison D, Bordachar P, Pierre B, Jais P, Pasquie JL, Hocini M, . 329. Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, Mauney J, . Legal F, Defaye P, Boveda S, Iesaka Y, Mabo P, Haissaguerre M. Outcome after Feirtag M, Mathias CJ, NOH301 Investigators. Droxidopa for neurogenic ortho- . implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a static hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology . multicenter study-part 2. Circulation 2013;128:1739–1747. 2014;83:328–335. . 350. O’Mahony C, Jichi F, Pavlou M, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, . 330. Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G. Droxidopa for the short- . Gimeno JR, Limongelli G, McKenna WJ, Omar RZ, Elliott PM, Hypertrophic term treatment of symptomatic neurogenic orthostatic hypotension in . Cardiomyopathy Outcomes Investigators. A novel clinical risk prediction model Parkinson’s disease (nOH306B). Mov Disord 2015;30:646–654. . for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur . 331. Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA, Kaufmann H, Droxidopa . Heart J 2014;35:2010–2020. 302 Investigators. Randomized withdrawal study of patients with symptomatic . 351. Corrado D, Calkins H, Link MS, Leoni L, Favale S, Bevilacqua M, Basso C, Ward neurogenic orthostatic hypotension responsive to droxidopa. Hypertension . D, Boriani G, Ricci R, Piccini JP, Dalal D, Santini M, Buja G, Iliceto S, Estes NA 2015;65:101–107. . III, Wichter T, McKenna WJ, Thiene G, Marcus FI. Prophylactic implantable 332. Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic . defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/ orthostatic hypotension associated with Parkinson’s disease (NOH306A). . dysplasia and no prior ventricular fibrillation or sustained ventricular tachycar- J Parkinsons Dis 2014;4:57–65. . dia. Circulation 2010;122:1144–1152. . 333. Elgebaly A, Abdelazeim B, Mattar O, Gadelkarim M, Salah R, Negida A. Meta- . 352. Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypo- . Barsheshet A, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, tension. Clin Auton Res 2016;26:171–180. . Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I, 334. Alboni P, Menozzi C, Brignole M, Paparella N, Gaggioli G, Lolli G, Cappato R. . International Long QT Syndrome Registry. Risk factors for recurrent syncope . Effects of permanent pacemaker and oral theophylline in sick sinus syndrome . and subsequent fatal or near-fatal events in children and adolescents with long the THEOPACE study: a randomized controlled trial. Circulation . QT syndrome. J Am Coll Cardiol 2011;57:941–950. 1997;96:260–266. . 353. Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, 335. Breivik K, Ohm OJ, Segadal L. Sick sinus syndrome treated with permanent . Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, pacemaker in 109 patients. A follow-up study. Acta Med Scand . Le Marec H, Wolpert C, Wilde AA. Long-term prognosis of patients diagnosed 1979;206:153–159. . with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. 336. Hartel G, Talvensaari T. Treatment of sinoatrial syndrome with permanent car- . Circulation 2010;121:635–643. . diac pacing in 90 patients. Acta Med Scand 1975;198:341–347. . 354. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS, 337. Rasmussen K. Chronic sinus node disease: natural course and indications for . Bongioanni S, Coccolo F, Estes NA, Barilla CS, Biagini E, Quarta G, Conte MR, pacing. Eur Heart J 1981;2:455–459. . Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic cardio- 338. Sasaki Y, Shimotori M, Akahane K, Yonekura H, Hirano K, Endoh R, Koike S, . myopathy. Circulation 2009;119:1703–1710. . Kawa S, Furuta S, Homma T. Long-term follow-up of patients with sick sinus . 355. Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di syndrome: a comparison of clinical aspects among unpaced, ventricular inhibited . Giovanni G, La Meir M, Wellens F, Czapla J, Wauters K, Levinstein M, Saitoh Y, paced, and physiologically paced groups. Pacing Clin Electrophysiol . Irfan G, Julia J, Pappaert G, Brugada P. Implantable cardioverter-defibrillator 1988;11:1575–1583. . therapy in Brugada syndrome: a 20-year single-center experience. J Am Coll . 339. Sgarbossa EB, Pinski SL, Jaeger FJ, Trohman RG, Maloney JD. Incidence and pre- . Cardiol 2015;65:879–888. dictors of syncope in paced patients with sick sinus syndrome. Pacing Clin . 356. Olde Nordkamp LR, Vink AS, Wilde AA, de Lange FJ, de Jong JS, Wieling W, Electrophysiol 1992;15:2055–2060. . van Dijk N, Tan HL. Syncope in Brugada syndrome: prevalence, clinical signifi- . 340. Ng Kam Chuen MJ, Kirkfeldt RE, Andersen HR, Nielsen JC. Syncope in paced . cance, and clues from history taking to distinguish arrhythmic from nonarrhyth- patients with sick sinus syndrome from the DANPACE trial: incidence, predic- . mic causes. Heart Rhythm 2015;12:367–375. tors and prognostic implication. Heart 2014;100:842–847. . 357. Olde Nordkamp LR, Wilde AA, Tijssen JG, Knops RE, van Dessel PF, de Groot 341. Langenfeld H, Grimm W, Maisch B, Kochsiek K. Course of symptoms and spon- . JR. The ICD for primary prevention in patients with inherited cardiac diseases: taneous ECG in pacemaker patients: a 5-year follow-up study. Pacing Clin . indications, use, and outcome: a comparison with secondary prevention. Circ Electrophysiol 1988;11:2198–2206. . Arrhythm Electrophysiol 2013;6:91–100. 342. Donateo P, Brignole M, Alboni P, Menozzi C, Raviele A, Del Rosso A, Dinelli . 358. Spezzacatene A, Sinagra G, Merlo M, Barbati G, Graw SL, Brun F, Slavov D, Di . M, Solano A, Bottoni N, Croci F. A standardized conventional evaluation of the . Lenarda A, Salcedo EE, Towbin JA, Saffitz JE, Marcus FI, Zareba W, Taylor MR, mechanism of syncope in patients with bundle branch block. Europace . Mestroni L, Familial Cardiomyopathy Registry. Arrhythmogenic Phenotype in 2002;4:357–360. . Dilated Cardiomyopathy: Natural History and Predictors of Life-Threatening 343. Azocar D, Ruiz-Granell R, Ferrero A, Martinez-Brotons A, Izquierdo M, . Arrhythmias. J Am Heart Assoc 2015;4:e002149. . Dominguez E, Palau P, Morell S, Garcia-Civera R. Syncope and bundle branch . 359. Russo AM, Verdino R, Schorr C, Nicholas M, Dias D, Hsia H, Callans D, block. Diagnostic yield of a stepped use of electrophysiology study and implant- . Marchlinski FE. Occurrence of implantable defibrillator events in patients with able loop recorders. Rev Esp Cardiol 2011;64:213–219. . syncope and nonischemic dilated cardiomyopathy. Am J Cardiol 344. Santini M, Castro A, Giada F, Ricci R, Inama G, Gaggioli G, Calo L, Orazi S, . 2001;88:1444–1446, A1449. Viscusi M, Chiodi L, Bartoletti A, Foglia-Manzillo G, Ammirati F, Loricchio ML, . 360. Phang RS, Kang D, Tighiouart H, Estes NA III, Link MS. High risk of ventricular Pedrinazzi C, Turreni F, Gasparini G, Accardi F, Raciti G, Raviele A. Prevention . arrhythmias in patients with nonischemic dilated cardiomyopathy presenting of syncope through permanent cardiac pacing in patients with bifascicular block . with syncope. Am J Cardiol 2006;97:416–420. . and syncope of unexplained origin: the PRESS study. Circ Arrhythm Electrophysiol . 361. Christiaans I, van Engelen K, van Langen IM, Birnie E, Bonsel GJ, Elliott PM, 2013;6:101–107. . Wilde AA. Risk stratification for sudden cardiac death in hypertrophic cardio- 345. Englund A, Bergfeldt L, Rehnqvist N, Astrom H, Rosenqvist M. Diagnostic value . myopathy: systematic review of clinical risk markers. Europace of programmed ventricular stimulation in patients with bifascicular block: a pro- . 2010;12:313–321. spective study of patients with and without syncope. J Am Coll Cardiol . 362. Corrado D, Wichter T, Link MS, Hauer R, Marchlinski F, Anastasakis A, Bauce 1995;26:1508–1515. . B, Basso C, Brunckhorst C, Tsatsopoulou A, Tandri H, Paul M, Schmied C,
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 68 ESC Guidelines
. Pelliccia A, Duru F, Protonotarios N, Estes NA III, McKenna WJ, Thiene G, . predictors, and the impact of co-morbidity and polypharmacy on the risk of Marcus FI, Calkins H. Treatment of arrhythmogenic right ventricular cardiomy- . recurrent syncope in patients <85 versus >/=85 years of age. Am J Cardiol . opathy/dysplasia: an international task force consensus statement. Eur Heart J . 2013;112:1610–1615. 2015;36:3227–3237. . 383. Mossello E, Pieraccioli M, Nesti N, Bulgaresi M, Lorenzi C, Caleri V, Tonon E, 363. Bhonsale A, James CA, Tichnell C, Murray B, Gagarin D, Philips B, Dalal D, . Cavallini MC, Baroncini C, Di Bari M, Baldasseroni S, Cantini C, Biagini CA, . Tedford R, Russell SD, Abraham T, Tandri H, Judge DP, Calkins H. Incidence . Marchionni N, Ungar A. Effects of low blood pressure in cognitively impaired and predictors of implantable cardioverter-defibrillator therapy in patients with . elderly patients treated with antihypertensive drugs. JAMA Intern Med arrhythmogenic right ventricular dysplasia/cardiomyopathy undergoing implant- . 2015;175:578–585. able cardioverter-defibrillator implantation for primary prevention. J Am Coll . 384. McLachlan CY, Yi M, Ling A, Jardine DL. Adverse drug events are a major cause Cardiol 2011;58:1485–1496. . of acute medical admission. Intern Med J 2014;44:633–638. 364. Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W, Qi M, Robinson JL. . 385. Ungar A, Mussi C, Ceccofiglio A, Bellelli G, Nicosia F, Bo M, Riccio D, Martone Risk of fatal arrhythmic events in long QT syndrome patients after syncope. . AM, Guadagno L, Noro G, Ghidoni G, Rafanelli M, Marchionni N, Abete P. . J Am Coll Cardiol 2010;55:783–788. . Etiology of syncope and unexplained falls in elderly adults with Dementia: 365. Giustetto C, Cerrato N, Ruffino E, Gribaudo E, Scrocco C, Barbonaglia L, . Syncope and Dementia (SYD) study. J Am Geriatr Soc 2016;64:1567–1573. Bianchi F, Bortnik M, Rossetti G, Carvalho P, Riccardi R, Castagno D, . 386. Ryan DJ, Harbison JA, Meaney JF, Rice CP, King-Kallimanis B, Kenny RA. Anselmino M, Bergamasco L, Gaita F. Etiological diagnosis, prognostic signifi- . Syncope causes transient focal neurological symptoms. QJM 2015;108:711–718. . cance and role of electrophysiological study in patients with Brugada ECG and . 387. Parry SW, Kenny RA. Drop attacks in older adults: systematic assessment has a syncope. Int J Cardiol 2017;241:188–193. . high diagnostic yield. J Am Geriatr Soc 2005;53:74–78. 366. Kubala M, Aissou L, Traulle S, Gugenheim AL, Hermida JS. Use of implantable . 388. Parry SW, Steen IN, Baptist M, Kenny RA. Amnesia for loss of consciousness in loop recorders in patients with Brugada syndrome and suspected risk of ven- . carotid sinus syndrome: implications for presentation with falls. J Am Coll Cardiol . tricular arrhythmia. Europace 2012;14:898–902. . 2005;45:1840–1843. 367. Delise P, Allocca G, Marras E, Giustetto C, Gaita F, Sciarra L, Calo L, . 389. O’Dwyer C, Bennett K, Langan Y, Fan CW, Kenny RA. Amnesia for loss of con- Proclemer A, Marziali M, Rebellato L, Berton G, Coro L, Sitta N. Risk stratifica- . sciousness is common in vasovagal syncope. Europace 2011;13:1040–1045. . tion in individuals with the Brugada type 1 ECG pattern without previous car- . 390. Rafanelli M, Ruffolo E, Chisciotti VM, Brunetti MA, Ceccofiglio A, Tesi F, diac arrest: usefulness of a combined clinical and electrophysiologic approach. . Morrione A, Marchionni N, Ungar A. Clinical aspects and diagnostic relevance Eur Heart J 2011;32:169–176. . of neuroautonomic evaluation in patients with unexplained falls. Aging Clin Exp 368. Maury P, Rollin A, Sacher F, Gourraud JB, Raczka F, Pasquie JL, Duparc A, . Res 2014;26:33–37. Mondoly P, Cardin C, Delay M, Derval N, Chatel S, Bongard V, Sadron M, . 391. Shaw FE, Bond J, Richardson DA, Dawson P, Steen IN, McKeith IG, Kenny RA. Denis A, Davy JM, Hocini M, Jais P, Jesel L, Haissaguerre M, Probst V. . Multifactorial intervention after a fall in older people with cognitive impairment Prevalence and prognostic role of various conduction disturbances in patients . and dementia presenting to the accident and emergency department: rando- . with the Brugada syndrome. Am J Cardiol 2013;112:1384–1389. . mised controlled trial. BMJ 2003;326:73. 369. Maury P, Sacher F, Gourraud JB, Pasquie JL, Raczka F, Bongard V, Duparc A, . 392. Frewen J, Finucane C, Savva GM, Boyle G, Kenny RA. Orthostatic hypotension Mondoly P, Sadron M, Chatel S, Derval N, Denis A, Cardin C, Davy JM, Hocini . is associated with lower cognitive performance in adults aged 50 plus with M, Jais P, Jesel L, Carrie D, Galinier M, Haissaguerre M, Probst V, Rollin A. . supine hypertension. J Gerontol A Biol Sci Med Sci 2014;69:878–885. . Increased Tpeak-Tend interval is highly and independently related to arrhythmic . 393. Robertson DA, Savva GM, Coen RF, Kenny RA. Cognitive function in the pre- events in Brugada syndrome. Heart Rhythm 2015;12:2469–2476. . frailty and frailty syndrome. J Am Geriatr Soc 2014;62:2118–2124. 370. Morita H, Kusano KF, Miura D, Nagase S, Nakamura K, Morita ST, Ohe T, . 394. Frewen J, King-Kallimanis B, Boyle G, Kenny RA. Recent syncope and unex- Zipes DP, Wu J. Fragmented QRS as a marker of conduction abnormality and a . plained falls are associated with poor cognitive performance. Age Ageing predictor of prognosis of Brugada syndrome. Circulation 2008;118:1697–1704. . 2015;44:282–286. 371. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, . 395. Robertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment–a review of Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M. . the evidence and causal mechanisms. Ageing Res Rev 2013;12:840–851. . Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed . 396. Kenny RA, Richardson DA, Steen N, Bexton RS, Shaw FE, Bond J. Carotid sinus ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol . syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE 2012;59:37–45. . PACE). J Am Coll Cardiol 2001;38:1491–1496. 372. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, car- . 397. Ungar A, Galizia G, Morrione A, Mussi C, Noro G, Ghirelli L, Masotti G, Rengo . dioinhibitory, and mixed carotid sinus syndrome in the elderly. Am J Med . F, Marchionni N, Abete P. Two-year morbidity and mortality in elderly patients 1993;95:203–208. . with syncope. Age Ageing 2011;40:696–702. 373. Ungar A, Mussi C, Del Rosso A, Noro G, Abete P, Ghirelli L, Cellai T, Landi A, . 398. Finucane C, O’Connell MD, Fan CW, Savva GM, Soraghan CJ, Nolan H, Cronin Salvioli G, Rengo F, Marchionni N, Masotti G, Italian Group for the Study of . H, Kenny RA. Age-related normative changes in phasic orthostatic blood pres- . Syncope in the Elderly. Diagnosis and characteristics of syncope in older . sure in a large population study: findings from The Irish Longitudinal Study on patients referred to geriatric departments. J Am Geriatr Soc 2006;54:1531–1536. . Ageing (TILDA). Circulation 2014;130:1780–1789. 374. Galizia G, Abete P, Mussi C, Noro G, Morrione A, Langellotto A, Landi A, . 399. DiMario FJ Jr. Prospective study of children with cyanotic and pallid breath- . Cacciatore F, Masotti G, Rengo F, Marchionni N, Ungar A. Role of early symp- . holding spells. Pediatrics 2001;107:265–269. toms in assessment of syncope in elderly people: results from the Italian group . 400. Vlahos AP, Kolettis TM. Family history of children and adolescents with neuro- for the study of syncope in the elderly. J Am Geriatr Soc 2009;57:18–23. . cardiogenic syncope. Pediatr Cardiol 2008;29:227. 375. Romme JJ, van Dijk N, Boer KR, Dekker LR, Stam J, Reitsma JB, Wieling W. . 401. Vlahos AP, Tzoufi M, Katsouras CS, Barka T, Sionti I, Michalis LK, Siamopoulou Influence of age and gender on the occurrence and presentation of reflex syn- . A, Kolettis TM. Provocation of neurocardiogenic syncope during head-up tilt cope. Clin Auton Res 2008;18:127–133. . testing in children: comparison between isoproterenol and nitroglycerin. 376. Bhangu JS, King-Kallimanis B, Cunningham C, Kenny RA. The relationship . Pediatrics 2007;119:e419–425. . between syncope, depression and anti-depressant use in older adults. Age . 402. McLeod KA, Wilson N, Hewitt J, Norrie J, Stephenson JB. Cardiac pacing for Ageing 2014;43:502–509. . severe childhood neurally mediated syncope with reflex anoxic seizures. Heart 377. Jansen S, Frewen J, Finucane C, de Rooij SE, van der Velde N, Kenny RA. AF is . 1999;82:721–725. associated with self-reported syncope and falls in a general population cohort. . 403. Raj V, Rowe AA, Fleisch SB, Paranjape SY, Arain AM, Nicolson SE. Psychogenic . Age Ageing 2015;44:598–603. . pseudosyncope: diagnosis and management. Auton Neurosci 2014;184:66–72. 378. Jansen S, Kenny RA, de Rooij SE, van der Velde N. Self-reported cardiovascular . 404. LaFrance WC Jr, Reuber M, Goldstein LH. Management of psychogenic nonepi- conditions are associated with falls and syncope in community-dwelling older . leptic seizures. Epilepsia 2013;54:53–67. adults. Age Ageing 2015;44:525–529. . 405. Saal DP, Overdijk MJ, Thijs RD, van Vliet IM, van Dijk JG. Long-term follow-up 379. Aronow WS. Heart disease and aging. Med Clin North Am 2006;90:849–862. . of psychogenic pseudosyncope. Neurology 2016;87:2214–2219. 380. Jansen S, Bhangu J, de Rooij S, Daams J, Kenny RA, van der Velde N. The . 406. LaFrance WC Jr, Baird GL, Barry JJ, Blum AS, Frank Webb A, Keitner GI, Association of Cardiovascular Disorders and Falls: a systematic review. JAm . Machan JT, Miller I, Szaflarski JP, NES Treatment Trial (NEST-T) Consortium. . Med Dir Assoc 2016;17:193–199. . Multicenter pilot treatment trial for psychogenic nonepileptic seizures: a 381. van der Velde N, van den Meiracker AH, Pols HA, Stricker BH, van der . randomized clinical trial. JAMA Psychiatry 2014;71:997–1005. Cammen TJ. Withdrawal of fall-risk-increasing drugs in older persons: effect on . 407. Benbadis SR, Chichkova R. Psychogenic pseudosyncope: an underestimated and tilt-table test outcomes. J Am Geriatr Soc 2007;55:734–739. . provable diagnosis. Epilepsy Behav 2006;9:106–110. 382. Ruwald MH, Hansen ML, Lamberts M, Hansen CM, Nume AK, Vinther M, . 408. Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK. Premotor signs and Kober L, Torp-Pedersen C, Hansen J, Gislason GH. Comparison of incidence, . symptoms of multiple system atrophy. Lancet Neurol 2012;11:361–368.
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018 ESC Guidelines 69
. 409. Siderowf A, Lang AE. Premotor Parkinson’s disease: concepts and definitions. . 426. Thijs RD, Kruit MC, van Buchem MA, Ferrari MD, Launer LJ, van Dijk JG. Mov Disord 2012;27:608–616. . Syncope in migraine: the population-based CAMERA study. Neurology 410. Hoefnagels WA, Padberg GW, Overweg J, van der Velde EA, Roos RA. . 2006;66:1034–1037. . Transient loss of consciousness: the value of the history for distinguishing seiz- . 427. Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers ure from syncope. J Neurol 1991;238:39–43. . GJ. The clinical features of cataplexy: a questionnaire study in narcolepsy patients 411. Benbadis SR, Wolgamuth BR, Goren H, Brener S, Fouad-Tarazi F. Value of . with and without hypocretin-1 deficiency. Sleep Med 2011;12:12–18. tongue biting in the diagnosis of seizures. Arch Intern Med 1995;155:2346–2349. . 428. Stevens DL, Matthews WB. Cryptogenic drop attacks: an affliction of women. . 412. van der Lende M, Surges R, Sander JW, Thijs RD. Cardiac arrhythmias during or . Br Med J 1973;1:439–442. after epileptic seizures. J Neurol Neurosurg Psychiatry 2016;87:69–74. . 429. Fanciulli A, Indelicato E, Wenning GK. Autonomic history taking and key symp- 413. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac . toms: where is the autonomic disease? In: A Fanciulli et al (eds). Bedside Approach . arrhythmias in focal epilepsy: a prospective long-term study. Lancet . to Autonomic Disorders A Clinical Tutor. Cham: Springer Verlag; 2017, 15–36. 2004;364:2212–2219. . 430. Abubakr A, Wambacq I. The diagnostic value of EEGs in patients with syncope. 414. Benditt DG, van Dijk G, Thijs RD. Ictal asystole: life-threatening vagal storm or . Epilepsy Behav 2005;6:433–434. a benign seizure self-termination mechanism? Circ Arrhythm Electrophysiol . 431. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med . 2015;8:11–14. . 2008;358:615–624. 415. Rocamora R, Kurthen M, Lickfett L, Von Oertzen J, Elger CE. Cardiac asystole in . 432. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles epilepsy: clinical and neurophysiologic features. Epilepsia 2003;44:179–185. . of patients seropositive for type 1 antineuronal nuclear autoantibodies. 416. Schuele SU, Bermeo AC, Alexopoulos AV, Locatelli ER, Burgess RC, Dinner . Neurology 1998;50:652–657. . DS, Foldvary-Schaefer N. Video-electrographic and clinical features in patients . 433. Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. with ictal asystole. Neurology 2007;69:434–441. . Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic 417. Ghearing GR, Munger TM, Jaffe AS, Benarroch EE, Britton JW. Clinical cues for . neuropathies. N Engl J Med 2000;343:847–855. . detecting ictal asystole. Clin Auton Res 2007;17:221–226. . 434. McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetyl- 418. Bestawros M, Darbar D, Arain A, Abou-Khalil B, Plummer D, Dupont WD, Raj . choline receptor autoantibody: oncological, neurological, and serological SR. Ictal asystole and ictal syncope: insights into clinical management. Circ . accompaniments. Arch Neurol 2009;66:735–741. Arrhythm Electrophysiol 2015;8:159–164. . 435. Dantas FG, Cavalcanti AP, Rodrigues Maciel BD, Ribeiro CD, Napy Charara 419. Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Sudden unexpected . GC, Lopes JM, Martins Filho PF, Junior LA. The role of EEG in patients with syn- death in epilepsy: people with nocturnal seizures may be at highest risk. . cope. J Clin Neurophysiol 2012;29:55–57. Epilepsia 2012;53:253–257. . 436. Kapoor WN, Karpf M, Maher Y, Miller RA, Levey GS. Syncope of unknown ori- . 420. Lamberts RJ, Blom MT, Wassenaar M, Bardai A, Leijten FS, de Haan GJ, Sander . gin. The need for a more cost-effective approach to its diagnosis evaluation. JW, Thijs RD, Tan HL. Sudden cardiac arrest in people with epilepsy in the . JAMA 1982;247:2687–2691. community: Circumstances and risk factors. Neurology 2015;85:212–218. . 437. Farwell DJ, Sulke AN. Does the use of a syncope diagnostic protocol 421. Horrocks IA, Nechay A, Stephenson JB, Zuberi SM. Anoxic-epileptic seizures: . improve the investigation and management of syncope? Heart 2004;90: . observational study of epileptic seizures induced by syncopes. Arch Dis Child . 52–58. 2005;90:1283–1287. . 438. Mendu ML, McAvay G, Lampert R, Stoehr J, Tinetti ME. Yield of diagnostic tests 422. Hennerici M, Klemm C, Rautenberg W. The subclavian steal phenomenon: a com- . in evaluating syncopal episodes in older patients. Arch Intern Med mon vascular disorder with rare neurologic deficits. Neurology 1988;38:669–673. . 2009;169:1299–1305. . 423. Melgar MA, Weinand ME. Thyrocervical trunk-external carotid artery bypass . 439. Schnipper JL, Ackerman RH, Krier JB, Honour M. Diagnostic yield and utility of for positional cerebral ischemia due to common carotid artery occlusion. . neurovascular ultrasonography in the evaluation of patients with syncope. Mayo Report of three cases. Neurosurg Focus 2003;14:e7. . Clin Proc 2005;80:480–488. . 424. Dobkin BH. Orthostatic hypotension as a risk factor for symptomatic occlusive . 440. Kadian-Dodov D, Papolos A, Olin JW. Diagnostic utility of carotid artery duplex cerebrovascular disease. Neurology 1989;39:30–34. . ultrasonography in the evaluation of syncope: a good test ordered for the 425. Savitz SI, Caplan LR. Vertebrobasilar disease. N Engl J Med 2005;352:2618–2626. . wrong reason. Eur Heart J Cardiovasc Imaging 2015;16:621–625. .
Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy037/4939241 by guest on 20 March 2018